Methods for the treatment of solid tumors

ABSTRACT

Described herein are combinations of ACK inhibitors and HDAC inhibitors in the treatment of diseases and disorders characterized by the presence or development of solid tumors.

CROSS-REFERENCE

This application claims the benefit of U.S. Application Ser. No.61/861,853, filed Aug. 2, 2013, which is incorporated herein byreference in its entirety.

SUMMARY OF THE INVENTION

Disclosed herein, in certain embodiments, are compositions comprising atherapeutically effective amount of an ACK inhibitor compound, atherapeutically effective amount of an HDAC inhibitor compound, and apharmaceutically acceptable excipient. In some embodiments, the ACKinhibitor compound is a BTK inhibitor. In some embodiments, the BTKinhibitor is an irreversible BTK inhibitor. In some embodiments, the ACKinhibitor is a compound of Formula (A):

wherein

A is independently selected from N or CR₅;

R₁ is H, L₂-(substituted or unsubstituted alkyl), L₂-(substituted orunsubstituted cycloalkyl), L₂-(substituted or unsubstituted alkenyl),L₂-(substituted or unsubstituted cycloalkenyl), L₂-(substituted orunsubstituted heterocycle), L₂-(substituted or unsubstitutedheteroaryl), or L₂-(substituted or unsubstituted aryl), where L₂ is abond, O, S, —S(═O), —S(═O)₂, C(═O), -(substituted or unsubstituted C₁-C₆alkyl), or -(substituted or unsubstituted C₂-C₆ alkenyl);R₂ and R₃ are independently selected from H, lower alkyl and substitutedlower alkyl;R₄ is L₃-X-L₄-G, wherein,L₃ is optional, and when present is a bond, optionally substituted orunsubstituted alkyl, optionally substituted or unsubstituted cycloalkyl,optionally substituted or unsubstituted alkenyl, optionally substitutedor unsubstituted alkynyl;X is optional, and when present is a bond, O, —C(═O), S, —S(═O),—S(═O)₂, —NH, —NR₉, —NHC(O), —C(O)NH, —NR₉C(O), —C(O)NR₉, —S(═O)₂NH,—NHS(═O)₂, —S(═O)₂NR₉—, —NR₉S(═O)₂, —OC(O)NH—, —NHC(O)O—, —OC(O)NR₉—,—NR₉C(O)O—, —CH═NO—, —ON═CH—, —NR₁₀C(O)NR₁₀—, heteroaryl, aryl,—NR₁₀C(═NR₁₁)NR₁₀—, —NR₁₀C(═NR₁₁)—, —C(═NR₁₁)NR₁₀—, —OC(═NR₁₁)—, or—C(═NR₁₁)O—;L₄ is optional, and when present is a bond, substituted or unsubstitutedalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted heterocycle;or L₃, X and L₄ taken together form a nitrogen containing heterocyclicring;G is

wherein,R₆, R₇ and R₈ are independently selected from among H, lower alkyl orsubstituted lower alkyl, lower heteroalkyl or substituted lowerheteroalkyl, substituted or unsubstituted lower cycloalkyl, andsubstituted or unsubstituted lower heterocycloalkyl;R₅ is H, halogen, -L₆-(substituted or unsubstituted C₁-C₃ alkyl),-L₆-(substituted or unsubstituted C₂-C₄ alkenyl), -L₆-(substituted orunsubstituted heteroaryl), or -L₆-(substituted or unsubstituted aryl),wherein L₆ is a bond, O, S, —S(═O), S(═O)₂, NH, C(O), —NHC(O)O,—OC(O)NH, —NHC(O), or —C(O)NH;each R₉ is independently selected from among H, substituted orunsubstituted lower alkyl, and substituted or unsubstituted lowercycloalkyl;each R₁₀ is independently H, substituted or unsubstituted lower alkyl,or substituted or unsubstituted lower cycloalkyl; ortwo R₁₀ groups can together form a 5-, 6-, 7-, or 8-memberedheterocyclic ring; orR₉ and R₁₀ can together form a 5-, 6-, 7-, or 8-membered heterocyclicring; oreach R₁₁ is independently selected from H, —S(═O)₂R₈, —S(═O)₂NH₂,—C(O)R₈, —CN, —NO₂, heteroaryl, or heteroalkyl.In some embodiments, the ACK inhibitor is(R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one(i.e. PCI-32765/ibrutinib).

In some embodiments, the ACK inhibitor is AVL-263 (AvilaTherapeutics/Celgene Corporation), AVL-292 (Avila Therapeutics/CelgeneCorporation), AVL-291 (Avila Therapeutics/Celgene Corporation),BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb),CGI-1746 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech),HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21,HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co.,Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (PekingUniversity), RN486 (Hoffmann-La Roche), or HM71224 (Hanmi PharmaceuticalCompany Limited). In some embodiments, the HDAC inhibitor is a compoundof Formula (B):

wherein:R¹ is hydrogen or alkyl;X is —O—, —NR²—, or —S(O)_(n) where n is 0-2 and R² is hydrogen oralkyl;Y is alkylene optionally substituted with cycloalkyl, optionallysubstituted phenyl, alkylthio, alkylsulfinyl, alkysulfonyl, optionallysubstituted phenylalkylthio, optionally substituted phenylalkylsulfonyl,hydroxy, or optionally substituted phenoxy;Ar¹ is phenylene or heteroarylene wherein said Ar¹ is optionallysubstituted with one or two groups independently selected from alkyl,halo, hydroxy, alkoxy, haloalkoxy, or haloalkyl;R³ is hydrogen, alkyl, hydroxyalkyl, or optionally substituted phenyl;andAr² is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl,heteroaralkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, orheterocycloalkylalkyl. In some embodiments, the HDAC inhibitor is3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide(i.e. PCI-24781/abexinostat)

In some embodiments, the HDAC inhibitor is3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide(i.e. PCI-24781/abexinostat)

and,the ACK inhibitor is(R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one(i.e. PCI-32765/ibrutinib)

In some embodiments, the composition is in the form of a solid dosageform. In some embodiments, the composition is in the form of a capsule.In some embodiments, the composition is in the form of a solution. Insome embodiments, the composition is in the form of a solution forintravenous administration. In some embodiments, the compositionscomprise 140 mg of ibrutinib. In some embodiments, the composition isfor use in treatment of a solid tumor. In some embodiments, thecomposition is for use in treatment of a sarcoma or carcinoma. In someembodiments, the composition is for use in treatment of a sarcoma. Insome embodiments, the composition is for use in treatment of acarcinoma. In some embodiments, the sarcoma is selected from alveolarrhabdomyosarcoma; alveolar soft part sarcoma; ameloblastoma;angiosarcoma; chondrosarcoma; chordoma; clear cell sarcoma of softtissue; dedifferentiated liposarcoma; desmoid; desmoplastic small roundcell tumor; embryonal rhabdomyosarcoma; epithelioid fibrosarcoma;epithelioid hemangioendothelioma; epithelioid sarcoma;esthesioneuroblastoma; Ewing sarcoma; extrarenal rhabdoid tumor;extraskeletal myxoid chondrosarcoma; extrasketetal osteosarcoma;fibrosarcoma; giant cell tumor; hemangiopericytoma; infantilefibrosarcoma; inflammatory myofibroblastic tumor; Kaposi sarcoma;leiomyosarcoma of bone; liposarcoma; liposarcoma of bone; malignantfibrous histiocytoma (MFH); malignant fibrous histiocytoma (MFH) ofbone; malignant mesenchymoma; malignant peripheral nerve sheath tumor;mesenchymal chondrosarcoma; myxofibrosarcoma; myxoid liposarcoma;myxoinflammatory fibroblastic sarcoma; neoplasms with perivascularepitheioid cell differentiation; osteosarcoma; parosteal osteosarcoma;neoplasm with perivascular epitheioid cell differentiation; periostealosteosarcoma; pleomorphic liposarcoma; pleomorphic rhabdomyosarcoma;PNET/extraskeletal Ewing tumor; rhabdomyosarcoma; round cellliposarcoma; small cell osteosarcoma; solitary fibrous tumor; synovialsarcoma; telangiectatic osteosarcoma. In some embodiments, the carcinomais selected from an adenocarcinoma, squamous cell carcinoma,adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, orsmall cell carcinoma. In some embodiments, the carcinoma is selectedfrom anal cancer; appendix cancer; bile duct cancer (i.e.,cholangiocarcinoma); bladder cancer; brain tumor; breast cancer;cervical cancer; colon cancer; cancer of Unknown Primary (CUP);esophageal cancer; eye cancer; fallopian tube cancer; kidney cancer;liver cancer; lung cancer; medulloblastoma; melanoma; oral cancer;ovarian cancer; pancreatic cancer; parathyroid disease; penile cancer;pituitary tumor; prostate cancer; rectal cancer; skin cancer; stomachcancer; testicular cancer; throat cancer; thyroid cancer; uterinecancer; vaginal cancer; or vulvar cancer. In some embodiments, thecarcinoma is breast cancer. In some embodiments, the breast cancer isinvasive ductal carcinoma, ductal carcinoma in situ, invasive lobularcarcinoma, or lobular carcinoma in situ. In some embodiments, thecarcinoma is pancreatic cancer. In some embodiments, the pancreaticcancer is adenocarcinoma, or islet cell carcinoma. In some embodiments,the carcinoma is colorectal cancer. In some embodiments, the colorectalcancer is adenocarcinoma. In some embodiments, the solid tumor is acolon polyp. In some embodiments, the colon polyp is associated withfamilial adenomatous polyposis. In some embodiments, the carcinoma isbladder cancer. In some embodiments, the bladder cancer is transitionalcell bladder cancer, squamous cell bladder cancer, or adenocarcinoma. Insome embodiments, the carcinoma is lung cancer. In some embodiments, thelung cancer is a non-small cell lung cancer. In some embodiments, thenon-small cell lung cancer is adenocarcinoma, squamous-cell lungcarcinoma, or large-cell lung carcinoma. In some embodiments, thenon-small cell lung cancer is large cell lung cancer. In someembodiments, the lung cancer is a small cell lung cancer. In someembodiments, the carcinoma is prostate cancer. In some embodiments, theprostate cancer is adenocarcinoma or small cell carcinoma. In someembodiments, the carcinoma is ovarian cancer. In some embodiments, theovarian cancer is epithelial ovarian cancer. In some embodiments, thecarcinoma is bile duct cancer. In some embodiments, the bile duct canceris proximal bile duct carcinoma or distal bile duct carcinoma. In someembodiments, the combination of ibrutinib and abexinostat is 5%, 10%,15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or 60% more efficacious thanadministration of abexinostat alone. In some embodiments, thecombination of the ibrutinib and abexinostat is 50% more efficaciousthan administration of abexinostat alone. In some embodiments, thecombination of ibrutinib and abexinostat is 5%, 10%, 15%, 20%, 25%, 30%,or 35% more efficacious than administration of ibrutinib alone. In someembodiments, the combination of ibrutinib and abexinostat is 25% moreefficacious than administration of ibrutinib alone.

Disclosed herein, in certain embodiments, are combinations of atherapeutically effective amount of an ACK inhibitor compound and atherapeutically effective amount of an HDAC inhibitor compound. In someembodiments, the ACK inhibitor compound is a BTK inhibitor. In someembodiments, the BTK inhibitor is an irreversible BTK inhibitor. In someembodiments, the ACK inhibitor is a compound of Formula (A):

whereinA is independently selected from N or CR₅;R₁ is H, L₂-(substituted or unsubstituted alkyl), L₂-(substituted orunsubstituted cycloalkyl), L₂-(substituted or unsubstituted alkenyl),L₂-(substituted or unsubstituted cycloalkenyl), L₂-(substituted orunsubstituted heterocycle), L₂-(substituted or unsubstitutedheteroaryl), or L₂-(substituted or unsubstituted aryl), where L₂ is abond, O, S, —S(═O), —S(═O)₂, C(═O), -(substituted or unsubstituted C₁-C₆alkyl), or -(substituted or unsubstituted C₂-C₆ alkenyl);R₂ and R₃ are independently selected from H, lower alkyl and substitutedlower alkyl;R₄ is L₃-X-L₄-G, wherein,L₃ is optional, and when present is a bond, optionally substituted orunsubstituted alkyl, optionally substituted or unsubstituted cycloalkyl,optionally substituted or unsubstituted alkenyl, optionally substitutedor unsubstituted alkynyl;X is optional, and when present is a bond, O, —C(═O), S, —S(═O),—S(═O)₂, —NH, —NR₉, —NHC(O), —C(O)NH, —NR₉C(O), —C(O)NR₉, —S(═O)₂NH,—NHS(═O)₂, —S(═O)₂NR₉—, —NR₉S(═O)₂, —OC(O)NH—, —NHC(O)O—, —OC(O)NR₉—,—NR₉C(O)O—, —CH═NO—, —ON═CH—, —NR₁₀C(O)NR₁₀—, heteroaryl, aryl,—NR₁₀C(═NR₁₁)NR₁₀—, —NR₁₀C(═NR₁₁)—, —C(═NR₁₁)NR₁₀—, —OC(═NR₁₁)—, or—C(═NR₁₁)O—;L₄ is optional, and when present is a bond, substituted or unsubstitutedalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted heterocycle;or L₃, X and L₄ taken together form a nitrogen containing heterocyclicring;G is

wherein,R₆, R₇ and R₈ are independently selected from among H, lower alkyl orsubstituted lower alkyl, lower heteroalkyl or substituted lowerheteroalkyl, substituted or unsubstituted lower cycloalkyl, andsubstituted or unsubstituted lower heterocycloalkyl;R₅ is H, halogen, -L₆-(substituted or unsubstituted C₁-C₃ alkyl),-L₆-(substituted or unsubstituted C₂-C₄ alkenyl), -L₆-(substituted orunsubstituted heteroaryl), or -L₆-(substituted or unsubstituted aryl),wherein L₆ is a bond, O, S, —S(═O), S(═O)₂, NH, C(O), —NHC(O)O,—OC(O)NH, —NHC(O), or —C(O)NH;each R₉ is independently selected from among H, substituted orunsubstituted lower alkyl, and substituted or unsubstituted lowercycloalkyl;each R₁₀ is independently H, substituted or unsubstituted lower alkyl,or substituted or unsubstituted lower cycloalkyl; ortwo R₁₀ groups can together form a 5-, 6-, 7-, or 8-memberedheterocyclic ring; orR₉ and R₁₀ can together form a 5-, 6-, 7-, or 8-membered heterocyclicring; oreach R₁₁ is independently selected from H, —S(═O)₂R₈, —S(═O)₂NH₂,—C(O)R₈, —CN, —NO₂, heteroaryl, or heteroalkyl.In some embodiments, the ACK inhibitor is(R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one(i.e. PCI-32765/ibrutinib).

In some embodiments, the ACK inhibitor is AVL-263 (AvilaTherapeutics/Celgene Corporation), AVL-292 (Avila Therapeutics/CelgeneCorporation), AVL-291 (Avila Therapeutics/Celgene Corporation),BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb),CGI-1746 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech),HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21,HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co.,Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (PekingUniversity), RN486 (Hoffmann-La Roche), or HM71224 (Hanmi PharmaceuticalCompany Limited). In some embodiments, the HDAC inhibitor is a compoundof Formula (B):

wherein:R¹ is hydrogen or alkyl;X is —O—, —NR²—, or —S(O)_(n) where n is 0-2 and R² is hydrogen oralkyl;Y is alkylene optionally substituted with cycloalkyl, optionallysubstituted phenyl, alkylthio, alkylsulfinyl, alkysulfonyl, optionallysubstituted phenylalkylthio, optionally substituted phenylalkylsulfonyl,hydroxy, or optionally substituted phenoxy;Ar¹ is phenylene or heteroarylene wherein said Ar¹ is optionallysubstituted with one or two groups independently selected from alkyl,halo, hydroxy, alkoxy, haloalkoxy, or haloalkyl;R³ is hydrogen, alkyl, hydroxyalkyl, or optionally substituted phenyl;andAr² is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl,heteroaralkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, orheterocycloalkylalkyl. In some embodiments, the HDAC inhibitor is3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide(i.e. PCI-24781/abexinostat)

In some embodiments, the HDAC inhibitor is3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide(i.e. PCI-24781/abexinostat)

and,the ACK inhibitor is(R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one(i.e. PCI-32765/ibrutinib)

In some embodiments the combination is administered in a solid dosageform. In some embodiments the combination is administered in a capsule.In some embodiments the combination is administered in a solution. Insome embodiments the combination is administered in a solution forintravenous administration. In some embodiments the combination,comprises 140 mg of ibrutinib. In some embodiments, the combination isfor use in treatment of a solid tumor. In some embodiments, thecombination is for use in treatment of a sarcoma or carcinoma. In someembodiments, the combination is for use in treatment of a sarcoma. Insome embodiments, the combination is for use in treatment of acarcinoma. In some embodiments, the sarcoma is selected from alveolarrhabdomyosarcoma; alveolar soft part sarcoma; ameloblastoma;angiosarcoma; chondrosarcoma; chordoma; clear cell sarcoma of softtissue; dedifferentiated liposarcoma; desmoid; desmoplastic small roundcell tumor; embryonal rhabdomyosarcoma; epithelioid fibrosarcoma;epithelioid hemangioendothelioma; epithelioid sarcoma;esthesioneuroblastoma; Ewing sarcoma; extrarenal rhabdoid tumor;extraskeletal myxoid chondrosarcoma; extrasketetal osteosarcoma;fibrosarcoma; giant cell tumor; hemangiopericytoma; infantilefibrosarcoma; inflammatory myofibroblastic tumor; Kaposi sarcoma;leiomyosarcoma of bone; liposarcoma; liposarcoma of bone; malignantfibrous histiocytoma (MFH); malignant fibrous histiocytoma (MFH) ofbone; malignant mesenchymoma; malignant peripheral nerve sheath tumor;mesenchymal chondrosarcoma; myxofibrosarcoma; myxoid liposarcoma;myxoinflammatory fibroblastic sarcoma; neoplasms with perivascularepitheioid cell differentiation; osteosarcoma; parosteal osteosarcoma;neoplasm with perivascular epitheioid cell differentiation; periostealosteosarcoma; pleomorphic liposarcoma; pleomorphic rhabdomyosarcoma;PNET/extraskeletal Ewing tumor; rhabdomyosarcoma; round cellliposarcoma; small cell osteosarcoma; solitary fibrous tumor; synovialsarcoma; telangiectatic osteosarcoma. In some embodiments, the carcinomais selected from an adenocarcinoma, squamous cell carcinoma,adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, orsmall cell carcinoma. In some embodiments, the carcinoma is selectedfrom anal cancer; appendix cancer; bile duct cancer (i.e.,cholangiocarcinoma); bladder cancer; brain tumor; breast cancer;cervical cancer; colon cancer; cancer of Unknown Primary (CUP);esophageal cancer; eye cancer; fallopian tube cancer; kidney cancer;liver cancer; lung cancer; medulloblastoma; melanoma; oral cancer;ovarian cancer; pancreatic cancer; parathyroid disease; penile cancer;pituitary tumor; prostate cancer; rectal cancer; skin cancer; stomachcancer; testicular cancer; throat cancer; thyroid cancer; uterinecancer; vaginal cancer; or vulvar cancer. In some embodiments, thecarcinoma is breast cancer. In some embodiments, the breast cancer isinvasive ductal carcinoma, ductal carcinoma in situ, invasive lobularcarcinoma, or lobular carcinoma in situ. In some embodiments, thecarcinoma is pancreatic cancer. In some embodiments, the pancreaticcancer is adenocarcinoma, or islet cell carcinoma. In some embodiments,the carcinoma is colorectal cancer. In some embodiments, the colorectalcancer is adenocarcinoma. In some embodiments, the solid tumor is acolon polyp. In some embodiments, the colon polyp is associated withfamilial adenomatous polyposis. In some embodiments, the carcinoma isbladder cancer. In some embodiments, the bladder cancer is transitionalcell bladder cancer, squamous cell bladder cancer, or adenocarcinoma. Insome embodiments, the carcinoma is lung cancer. In some embodiments, thelung cancer is a non-small cell lung cancer. In some embodiments, thenon-small cell lung cancer is adenocarcinoma, squamous-cell lungcarcinoma, or large-cell lung carcinoma. In some embodiments, thenon-small cell lung cancer is large cell lung cancer. In someembodiments, the lung cancer is a small cell lung cancer. In someembodiments, the carcinoma is prostate cancer. In some embodiments, theprostate cancer is adenocarcinoma or small cell carcinoma. In someembodiments, the carcinoma is ovarian cancer. In some embodiments, theovarian cancer is epithelial ovarian cancer. In some embodiments, thecarcinoma is bile duct cancer. In some embodiments, the bile duct canceris proximal bile duct carcinoma or distal bile duct carcinoma. In someembodiments, the combination of ibrutinib and abexinostat is 5%, 10%,15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or 60% more efficacious thanadministration of abexinostat alone. In some embodiments, thecombination of the ibrutinib and abexinostat is 50% more efficaciousthan administration of abexinostat alone. In some embodiments, thecombination of ibrutinib and abexinostat is 5%, 10%, 15%, 20%, 25%, 30%,or 35% more efficacious than administration of ibrutinib alone. In someembodiments, the combination of ibrutinib and abexinostat is 25% moreefficacious than administration of ibrutinib alone. In some embodimentsthe combination is administered in a unified dosage form or separatedosage forms. In some embodiments the combination is administeredsimultaneously or sequentially.

Disclosed herein, in certain embodiments, are methods for treating asolid tumor comprising co-administering to an individual in need thereofan ACK inhibitor compound and an HDAC inhibitor compound. In someembodiments, the ACK inhibitor is(R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one(i.e. PCI-32765/ibrutinib)

In some embodiments, the HDAC inhibitor is3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide(i.e. PCI-24781/abexinostat)

In some embodiments, the solid tumor is a carcinoma. In someembodiments, the carcinoma is breast cancer. In some embodiments, thecarcinoma is pancreatic cancer. In some embodiments, the carcinoma iscolorectal cancer. In some embodiments, the carcinoma is bladder cancer.In some embodiments, the carcinoma is lung cancer. In some embodiments,the lung cancer is a non-small cell lung cancer. In some embodiments,the lung cancer is a large cell lung cancer. In some embodiments, thecarcinoma is prostate cancer. In some embodiments, the carcinoma isovarian cancer. In some embodiments, the carcinoma is bile duct cancer.In some embodiments, co-administration of the ACK inhibitor and the HDACinhibitor is 50% more efficacious than administration of the HDACinhibitor alone. In some embodiments, co-administration of the ACKinhibitor and the HDAC inhibitor is 25% more efficacious thanadministration of the ACK inhibitor alone. In some embodiments, the ACKinhibitor and the HDAC inhibitor are administered in a unified dosageform or separate dosage forms. In some embodiments, the ACK inhibitorand the HDAC inhibitor are administered simultaneously or sequentially.

Disclosed herein, in certain embodiments, are methods for treating asolid tumor comprising co-administering to an individual in need thereofan ACK inhibitor compound and an HDAC inhibitor compound. In someembodiments, the ACK inhibitor compound is a BTK inhibitor. In someembodiments, the BTK inhibitor is an irreversible BTK inhibitor. In someembodiments, the ACK inhibitor is a compound of Formula (A):

whereinA is independently selected from N or CR₅;R₁ is H, L₂-(substituted or unsubstituted alkyl), L₂-(substituted orunsubstituted cycloalkyl), L₂-(substituted or unsubstituted alkenyl),L₂-(substituted or unsubstituted cycloalkenyl), L₂-(substituted orunsubstituted heterocycle), L₂-(substituted or unsubstitutedheteroaryl), or L₂-(substituted or unsubstituted aryl), where L₂ is abond, O, S, —S(═O), —S(═O)₂, C(═O), -(substituted or unsubstituted C₁-C₆alkyl), or -(substituted or unsubstituted C₂-C₆ alkenyl);R₂ and R₃ are independently selected from H, lower alkyl and substitutedlower alkyl;R₄ is L₃-X-L₄-G, wherein,L₃ is optional, and when present is a bond, optionally substituted orunsubstituted alkyl, optionally substituted or unsubstituted cycloalkyl,optionally substituted or unsubstituted alkenyl, optionally substitutedor unsubstituted alkynyl;X is optional, and when present is a bond, O, —C(═O), S, —S(═O),—S(═O)₂, —NH, —NR₉, —NHC(O), —C(O)NH, —NR₉C(O), —C(O)NR₉, —S(═O)₂NH,—NHS(═O)₂, —S(═O)₂NR₉—, —NR₉S(═O)₂, —OC(O)NH—, —NHC(O)O—, —OC(O)NR₉—,—NR₉C(O)O—, —CH═NO—, —ON═CH—, —NR₁₀C(O)NR₁₀—, heteroaryl, aryl,—NR₁₀C(═NR₁₁)NR₁₀—, —C(═NR₁₁)NR₁₀—, —OC(═NR₁₁)—, or —C(═NR₁₁)O—;L₄ is optional, and when present is a bond, substituted or unsubstitutedalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted heterocycle;or L₃, X and L₄ taken together form a nitrogen containing heterocyclicring;G is

wherein,R₆, R₇ and R₈ are independently selected from among H, lower alkyl orsubstituted lower alkyl, lower heteroalkyl or substituted lowerheteroalkyl, substituted or unsubstituted lower cycloalkyl, andsubstituted or unsubstituted lower heterocycloalkyl;R₅ is H, halogen, -L₆-(substituted or unsubstituted C₁-C₃ alkyl),-L₆-(substituted or unsubstituted C₂-C₄ alkenyl), -L₆-(substituted orunsubstituted heteroaryl), or -L₆-(substituted or unsubstituted aryl),wherein L₆ is a bond, O, S, —S(═O), S(═O)₂, NH, C(O), —NHC(O)O,—OC(O)NH, —NHC(O), or —C(O)NH;each R₉ is independently selected from among H, substituted orunsubstituted lower alkyl, and substituted or unsubstituted lowercycloalkyl;each R₁₀ is independently H, substituted or unsubstituted lower alkyl,or substituted or unsubstituted lower cycloalkyl; ortwo R₁₀ groups can together form a 5-, 6-, 7-, or 8-memberedheterocyclic ring; orR₉ and R₁₀ can together form a 5-, 6-, 7-, or 8-membered heterocyclicring; oreach R₁₁ is independently selected from H, —S(═O)₂R₈, —S(═O)₂NH₂,—C(O)R₈, —CN, —NO₂, heteroaryl, or heteroalkyl.

In some embodiments, the ACK inhibitor is(R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one(i.e. PCI-32765/ibrutinib).

In some embodiments, the ACK inhibitor is AVL-263 (AvilaTherapeutics/Celgene Corporation), AVL-292 (Avila Therapeutics/CelgeneCorporation), AVL-291 (Avila Therapeutics/Celgene Corporation),BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb),CGI-1746 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech),HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21,HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co.,Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (PekingUniversity), RN486 (Hoffmann-La Roche), or HM71224 (Hanmi PharmaceuticalCompany Limited). In some embodiments, the HDAC inhibitor is a compoundof Formula (B):

wherein:R¹ is hydrogen or alkyl;X is —O—, —NR²—, or —S(O)_(n) where n is 0-2 and R² is hydrogen oralkyl;Y is alkylene optionally substituted with cycloalkyl, optionallysubstituted phenyl, alkylthio, alkylsulfinyl, alkysulfonyl, optionallysubstituted phenylalkylthio, optionally substituted phenylalkylsulfonyl,hydroxy, or optionally substituted phenoxy;Ar¹ is phenylene or heteroarylene wherein said Ar¹ is optionallysubstituted with one or two groups independently selected from alkyl,halo, hydroxy, alkoxy, haloalkoxy, or haloalkyl;R³ is hydrogen, alkyl, hydroxyalkyl, or optionally substituted phenyl;andAr² is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl,heteroaralkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, orheterocycloalkylalkyl. In some embodiments, the HDAC inhibitor is3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide(i.e. PCI-24781/abexinostat)

In some embodiments, the solid tumor is a sarcoma or carcinoma. In someembodiments, the solid tumor is a sarcoma. In some embodiments, thesolid tumor is a carcinoma. In some embodiments, the sarcoma is selectedfrom alveolar rhabdomyosarcoma; alveolar soft part sarcoma;ameloblastoma; angiosarcoma; chondrosarcoma; chordoma; clear cellsarcoma of soft tissue; dedifferentiated liposarcoma; desmoid;desmoplastic small round cell tumor; embryonal rhabdomyosarcoma;epithelioid fibrosarcoma; epithelioid hemangioendothelioma; epithelioidsarcoma; esthesioneuroblastoma; Ewing sarcoma; extrarenal rhabdoidtumor; extraskeletal myxoid chondrosarcoma; extrasketetal osteosarcoma;fibrosarcoma; giant cell tumor; hemangiopericytoma; infantilefibrosarcoma; inflammatory myofibroblastic tumor; Kaposi sarcoma;leiomyosarcoma of bone; liposarcoma; liposarcoma of bone; malignantfibrous histiocytoma (MFH); malignant fibrous histiocytoma (MFH) ofbone; malignant mesenchymoma; malignant peripheral nerve sheath tumor;mesenchymal chondrosarcoma; myxofibrosarcoma; myxoid liposarcoma;myxoinflammatory fibroblastic sarcoma; neoplasms with perivascularepitheioid cell differentiation; osteosarcoma; parosteal osteosarcoma;neoplasm with perivascular epitheioid cell differentiation; periostealosteosarcoma; pleomorphic liposarcoma; pleomorphic rhabdomyosarcoma;PNET/extraskeletal Ewing tumor; rhabdomyosarcoma; round cellliposarcoma; small cell osteosarcoma; solitary fibrous tumor; synovialsarcoma; telangiectatic osteosarcoma. In some embodiments, the carcinomais selected from an adenocarcinoma, squamous cell carcinoma,adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, orsmall cell carcinoma. In some embodiments, the carcinoma is selectedfrom anal cancer; appendix cancer; bile duct cancer (i.e.,cholangiocarcinoma); bladder cancer; brain tumor; breast cancer;cervical cancer; colon cancer; cancer of Unknown Primary (CUP);esophageal cancer; eye cancer; fallopian tube cancer; kidney cancer;liver cancer; lung cancer; medulloblastoma; melanoma; oral cancer;ovarian cancer; pancreatic cancer; parathyroid disease; penile cancer;pituitary tumor; prostate cancer; rectal cancer; skin cancer; stomachcancer; testicular cancer; throat cancer; thyroid cancer; uterinecancer; vaginal cancer; or vulvar cancer. In some embodiments, thecarcinoma is breast cancer. In some embodiments, the breast cancer isinvasive ductal carcinoma, ductal carcinoma in situ, invasive lobularcarcinoma, or lobular carcinoma in situ. In some embodiments, thecarcinoma is pancreatic cancer. In some embodiments, the pancreaticcancer is adenocarcinoma, or islet cell carcinoma. In some embodiments,the carcinoma is colorectal cancer. In some embodiments, the colorectalcancer is adenocarcinoma. In some embodiments, the solid tumor is acolon polyp. In some embodiments, the colon polyp is associated withfamilial adenomatous polyposis. In some embodiments, the carcinoma isbladder cancer. In some embodiments, the bladder cancer is transitionalcell bladder cancer, squamous cell bladder cancer, or adenocarcinoma. Insome embodiments, the carcinoma is lung cancer. In some embodiments, thelung cancer is a non-small cell lung cancer. In some embodiments, thenon-small cell lung cancer is adenocarcinoma, squamous-cell lungcarcinoma, or large-cell lung carcinoma. In some embodiments, the lungcancer is a small cell lung cancer. In some embodiments, the carcinomais prostate cancer. In some embodiments, the prostate cancer isadenocarcinoma or small cell carcinoma. In some embodiments, thecarcinoma is ovarian cancer. In some embodiments, the ovarian cancer isepithelial ovarian cancer. In some embodiments, the carcinoma is bileduct cancer. In some embodiments, the bile duct cancer is proximal bileduct carcinoma or distal bile duct carcinoma. In some embodiments,co-administration of the ACK inhibitor and the HDAC inhibitor is 5%,10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or 60% more efficaciousthan administration of the HDAC inhibitor alone. In some embodiments,co-administration of the ACK inhibitor and the HDAC inhibitor is 50%more efficacious than administration of the HDAC inhibitor alone. Insome embodiments, co-administration of the ACK inhibitor and the HDACinhibitor is 5%, 10%, 15%, 20%, 25%, 30%, or 35% more efficacious thanadministration of the ACK inhibitor alone. In some embodiments,co-administration of the ACK inhibitor and the HDAC inhibitor is 25%more efficacious than administration of the ACK inhibitor alone. In someembodiments, the ACK inhibitor and the HDAC inhibitor are administeredin a unified dosage form or separate dosage forms. In some embodiments,the ACK inhibitor and the HDAC inhibitor are administered simultaneouslyor sequentially.

Disclosed herein, in certain embodiments, are methods for treating asolid tumor comprising co-administering to an individual in need thereofan HDAC inhibitor compound and(R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one(i.e. PCI-32765/ibrutinib).

In some embodiments, the HDAC inhibitor is a compound of Formula (B):

wherein:R¹ is hydrogen or alkyl;X is —O—, —NR²—, or —S(O)_(n) where n is 0-2 and R² is hydrogen oralkyl;Y is alkylene optionally substituted with cycloalkyl, optionallysubstituted phenyl, alkylthio, alkylsulfinyl, alkysulfonyl, optionallysubstituted phenylalkylthio, optionally substituted phenylalkylsulfonyl,hydroxy, or optionally substituted phenoxy;Ar¹ is phenylene or heteroarylene wherein said Ar¹ is optionallysubstituted with one or two groups independently selected from alkyl,halo, hydroxy, alkoxy, haloalkoxy, or haloalkyl;R³ is hydrogen, alkyl, hydroxyalkyl, or optionally substituted phenyl;andAr² is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl,heteroaralkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, orheterocycloalkylalkyl.In some embodiments, the HDAC inhibitor is3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide(i.e. PCI-24781/abexinostat)

In some embodiments, the solid tumor is a sarcoma or carcinoma. In someembodiments, the solid tumor is a sarcoma. In some embodiments, thesolid tumor is a carcinoma. In some embodiments, the sarcoma is selectedfrom alveolar rhabdomyosarcoma; alveolar soft part sarcoma;ameloblastoma; angiosarcoma; chondrosarcoma; chordoma; clear cellsarcoma of soft tissue; dedifferentiated liposarcoma; desmoid;desmoplastic small round cell tumor; embryonal rhabdomyosarcoma;epithelioid fibrosarcoma; epithelioid hemangioendothelioma; epithelioidsarcoma; esthesioneuroblastoma; Ewing sarcoma; extrarenal rhabdoidtumor; extraskeletal myxoid chondrosarcoma; extrasketetal osteosarcoma;fibrosarcoma; giant cell tumor; hemangiopericytoma; infantilefibrosarcoma; inflammatory myofibroblastic tumor; Kaposi sarcoma;leiomyosarcoma of bone; liposarcoma; liposarcoma of bone; malignantfibrous histiocytoma (MFH); malignant fibrous histiocytoma (MFH) ofbone; malignant mesenchymoma; malignant peripheral nerve sheath tumor;mesenchymal chondrosarcoma; myxofibrosarcoma; myxoid liposarcoma;myxoinflammatory fibroblastic sarcoma; neoplasms with perivascularepitheioid cell differentiation; osteosarcoma; parosteal osteosarcoma;neoplasm with perivascular epitheioid cell differentiation; periostealosteosarcoma; pleomorphic liposarcoma; pleomorphic rhabdomyosarcoma;PNET/extraskeletal Ewing tumor; rhabdomyosarcoma; round cellliposarcoma; small cell osteosarcoma; solitary fibrous tumor; synovialsarcoma; telangiectatic osteosarcoma. In some embodiments, the carcinomais selected from an adenocarcinoma, squamous cell carcinoma,adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, orsmall cell carcinoma. In some embodiments, the carcinoma is selectedfrom anal cancer; appendix cancer; bile duct cancer (i.e.,cholangiocarcinoma); bladder cancer; brain tumor; breast cancer;cervical cancer; colon cancer; cancer of Unknown Primary (CUP);esophageal cancer; eye cancer; fallopian tube cancer; kidney cancer;liver cancer; lung cancer; medulloblastoma; melanoma; oral cancer;ovarian cancer; pancreatic cancer; parathyroid disease; penile cancer;pituitary tumor; prostate cancer; rectal cancer; skin cancer; stomachcancer; testicular cancer; throat cancer; thyroid cancer; uterinecancer; vaginal cancer; or vulvar cancer. In some embodiments, thecarcinoma is breast cancer. In some embodiments, the breast cancer isinvasive ductal carcinoma, ductal carcinoma in situ, invasive lobularcarcinoma, or lobular carcinoma in situ. In some embodiments, thecarcinoma is pancreatic cancer. In some embodiments, the pancreaticcancer is adenocarcinoma, or islet cell carcinoma. In some embodiments,the carcinoma is colorectal cancer. In some embodiments, the colorectalcancer is adenocarcinoma. In some embodiments, the solid tumor is acolon polyp. In some embodiments, the colon polyp is associated withfamilial adenomatous polyposis. In some embodiments, the carcinoma isbladder cancer. In some embodiments, the bladder cancer is transitionalcell bladder cancer, squamous cell bladder cancer, or adenocarcinoma. Insome embodiments, the carcinoma is lung cancer. In some embodiments, thelung cancer is a non-small cell lung cancer. In some embodiments, thenon-small cell lung cancer is adenocarcinoma, squamous-cell lungcarcinoma, or large-cell lung carcinoma. In some embodiments, the lungcancer is a small cell lung cancer. In some embodiments, the carcinomais prostate cancer. In some embodiments, the prostate cancer isadenocarcinoma or small cell carcinoma. In some embodiments, thecarcinoma is ovarian cancer. In some embodiments, the ovarian cancer isepithelial ovarian cancer. In some embodiments, the carcinoma is bileduct cancer. In some embodiments, the bile duct cancer is proximal bileduct carcinoma or distal bile duct carcinoma. In some embodiments,co-administration of ibrutinib and the HDAC inhibitor is 5%, 10%, 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or 60% more efficacious thanadministration of the HDAC inhibitor alone. In some embodiments,co-administration of ibrutinib and the HDAC inhibitor is 50% moreefficacious than administration of the HDAC inhibitor alone. In someembodiments, co-administration of ibrutinib and the HDAC inhibitor is5%, 10%, 15%, 20%, 25%, 30%, or 35% more efficacious than administrationof ibrutinib alone. In some embodiments, co-administration of ibrutiniband the HDAC inhibitor is 25% more efficacious than administration ofibrutinib alone. In some embodiments, ibrutinib and the HDAC inhibitorare administered in a unified dosage form or separate dosage forms. Insome embodiments, ibrutinib and the HDAC inhibitor are administeredsimultaneously or sequentially.

Disclosed herein, in certain embodiments, are methods for treating asolid tumor comprising co-administering to an individual in need thereofan ACK inhibitor compound and3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide(i.e. PCI-24781/abexinostat)

In some embodiments, the ACK inhibitor compound is a BTK inhibitor. Insome embodiments, the BTK inhibitor is an irreversible BTK inhibitor. Insome embodiments, the ACK inhibitor is a compound of Formula (A):

whereinA is independently selected from N or CR₅;R₁ is H, L₂-(substituted or unsubstituted alkyl), L₂-(substituted orunsubstituted cycloalkyl), L₂-(substituted or unsubstituted alkenyl),L₂-(substituted or unsubstituted cycloalkenyl), L₂-(substituted orunsubstituted heterocycle), L₂-(substituted or unsubstitutedheteroaryl), or L₂-(substituted or unsubstituted aryl), where L₂ is abond, O, S, —S(═O), —S(═O)₂, C(═O), -(substituted or unsubstituted C₁-C₆alkyl), or -(substituted or unsubstituted C₂-C₆ alkenyl);R₂ and R₃ are independently selected from H, lower alkyl and substitutedlower alkyl;R₄ is L₃-X-L₄-G, wherein,L₃ is optional, and when present is a bond, optionally substituted orunsubstituted alkyl, optionally substituted or unsubstituted cycloalkyl,optionally substituted or unsubstituted alkenyl, optionally substitutedor unsubstituted alkynyl;X is optional, and when present is a bond, O, —C(═O), S, —S(═O),—S(═O)₂, —NH, —NR₉, —NHC(O), —C(O)NH, —NR₉C(O), —C(O)NR₉, —S(═O)₂NH,—NHS(═O)₂, —S(═O)₂NR₉—, —NR₉S(═O)₂, —OC(O)NH—, —NHC(O)O—, —OC(O)NR₉—,—NR₉C(O)O—, —CH═NO—, —ON═CH—, —NR₁₀C(O)NR₁₀—, heteroaryl, aryl,—NR₁₀C(═NR₁₁)NR₁₀—, —C(═NR₁₁)NR₁₀—, —OC(═NR₁₁)—, or —C(═NR₁₁)O—;L₄ is optional, and when present is a bond, substituted or unsubstitutedalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted heterocycle;or L₃, X and L₄ taken together form a nitrogen containing heterocyclicring;G is

wherein,R₆, R₇ and R₈ are independently selected from among H, lower alkyl orsubstituted lower alkyl, lower heteroalkyl or substituted lowerheteroalkyl, substituted or unsubstituted lower cycloalkyl, andsubstituted or unsubstituted lower heterocycloalkyl;R₅ is H, halogen, -L₆-(substituted or unsubstituted C₁-C₃ alkyl),-L₆-(substituted or unsubstituted C₂-C₄ alkenyl), -L₆-(substituted orunsubstituted heteroaryl), or -L₆-(substituted or unsubstituted aryl),wherein L₆ is a bond, O, S, —S(═O), S(═O)₂, NH, C(O), —NHC(O)O,—OC(O)NH, —NHC(O), or —C(O)NH;each R₉ is independently selected from among H, substituted orunsubstituted lower alkyl, and substituted or unsubstituted lowercycloalkyl;each R₁₀ is independently H, substituted or unsubstituted lower alkyl,or substituted or unsubstituted lower cycloalkyl; ortwo R₁₀ groups can together form a 5-, 6-, 7-, or 8-memberedheterocyclic ring; orR₉ and R₁₀ can together form a 5-, 6-, 7-, or 8-membered heterocyclicring; oreach R₁₁ is independently selected from H, —S(═O)₂R₈, —S(═O)₂NH₂,—C(O)R₈, —CN, —NO₂, heteroaryl, or heteroalkyl. In some embodiments, theACK inhibitor is(R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one(i.e. PCI-32765/ibrutinib)

In some embodiments, the ACK inhibitor is AVL-263 (AvilaTherapeutics/Celgene Corporation), AVL-292 (Avila Therapeutics/CelgeneCorporation), AVL-291 (Avila Therapeutics/Celgene Corporation),BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb),CGI-1746 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech),HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21,HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co.,Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (PekingUniversity), RN486 (Hoffmann-La Roche), or HM71224 (Hanmi PharmaceuticalCompany Limited). In some embodiments, the solid tumor is a sarcoma orcarcinoma. In some embodiments, the solid tumor is a sarcoma. In someembodiments, the solid tumor is a carcinoma. In some embodiments, thesarcoma is selected from alveolar rhabdomyosarcoma; alveolar soft partsarcoma; ameloblastoma; angiosarcoma; chondrosarcoma; chordoma; clearcell sarcoma of soft tissue; dedifferentiated liposarcoma; desmoid;desmoplastic small round cell tumor; embryonal rhabdomyosarcoma;epithelioid fibrosarcoma; epithelioid hemangioendothelioma; epithelioidsarcoma; esthesioneuroblastoma; Ewing sarcoma; extrarenal rhabdoidtumor; extraskeletal myxoid chondrosarcoma; extrasketetal osteosarcoma;fibrosarcoma; giant cell tumor; hemangiopericytoma; infantilefibrosarcoma; inflammatory myofibroblastic tumor; Kaposi sarcoma;leiomyosarcoma of bone; liposarcoma; liposarcoma of bone; malignantfibrous histiocytoma (MFH); malignant fibrous histiocytoma (MFH) ofbone; malignant mesenchymoma; malignant peripheral nerve sheath tumor;mesenchymal chondrosarcoma; myxofibrosarcoma; myxoid liposarcoma;myxoinflammatory fibroblastic sarcoma; neoplasms with perivascularepitheioid cell differentiation; osteosarcoma; parosteal osteosarcoma;neoplasm with perivascular epitheioid cell differentiation; periostealosteosarcoma; pleomorphic liposarcoma; pleomorphic rhabdomyosarcoma;PNET/extraskeletal Ewing tumor; rhabdomyosarcoma; round cellliposarcoma; small cell osteosarcoma; solitary fibrous tumor; synovialsarcoma; telangiectatic osteosarcoma. In some embodiments, the carcinomais selected from an adenocarcinoma, squamous cell carcinoma,adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, orsmall cell carcinoma. In some embodiments, the carcinoma is selectedfrom anal cancer; appendix cancer; bile duct cancer (i.e.,cholangiocarcinoma); bladder cancer; brain tumor; breast cancer;cervical cancer; colon cancer; cancer of Unknown Primary (CUP);esophageal cancer; eye cancer; fallopian tube cancer; kidney cancer;liver cancer; lung cancer; medulloblastoma; melanoma; oral cancer;ovarian cancer; pancreatic cancer; parathyroid disease; penile cancer;pituitary tumor; prostate cancer; rectal cancer; skin cancer; stomachcancer; testicular cancer; throat cancer; thyroid cancer; uterinecancer; vaginal cancer; or vulvar cancer. In some embodiments, thecarcinoma is breast cancer. In some embodiments, the breast cancer isinvasive ductal carcinoma, ductal carcinoma in situ, invasive lobularcarcinoma, or lobular carcinoma in situ. In some embodiments, thecarcinoma is pancreatic cancer. In some embodiments, the pancreaticcancer is adenocarcinoma, or islet cell carcinoma. In some embodiments,the carcinoma is colorectal cancer. In some embodiments, the colorectalcancer is adenocarcinoma. In some embodiments, the solid tumor is acolon polyp. In some embodiments, the colon polyp is associated withfamilial adenomatous polyposis. In some embodiments, the carcinoma isbladder cancer. In some embodiments, the bladder cancer is transitionalcell bladder cancer, squamous cell bladder cancer, or adenocarcinoma. Insome embodiments, the carcinoma is lung cancer. In some embodiments, thelung cancer is a non-small cell lung cancer. In some embodiments, thenon-small cell lung cancer is adenocarcinoma, squamous-cell lungcarcinoma, or large-cell lung carcinoma. In some embodiments, the lungcancer is a small cell lung cancer. In some embodiments, the carcinomais prostate cancer. In some embodiments, the prostate cancer isadenocarcinoma or small cell carcinoma. In some embodiments, thecarcinoma is ovarian cancer. In some embodiments, the ovarian cancer isepithelial ovarian cancer. In some embodiments, the carcinoma is bileduct cancer. In some embodiments, the bile duct cancer is proximal bileduct carcinoma or distal bile duct carcinoma. In some embodiments,co-administration of the abexinostat and the ACK inhibitor is 5%, 10%,15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or 60% more efficacious thanadministration of abexinostat alone. In some embodiments,co-administration of the abexinostat and the ACK inhibitor is 50% moreefficacious than administration of abexinostat alone. In someembodiments, co-administration of the abexinostat and the ACK inhibitoris 5%, 10%, 15%, 20%, 25%, 30%, or 35% more efficacious thanadministration of the ACK inhibitor alone. In some embodiments,co-administration of the abexinostat and the ACK inhibitor is 25% moreefficacious than administration of the ACK inhibitor alone. In someembodiments, the ACK inhibitor and abexinostat are administered in aunified dosage form or separate dosage forms. In some embodiments, theACK inhibitor and abexinostat are administered simultaneously orsequentially.

Disclosed herein, in certain embodiments, are methods for treating asolid tumor comprising administering to an individual in need thereof acombination of(R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one(i.e. PCI-32765/ibrutinib)

and3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide(i.e. PCI-24781/abexinostat)

In some embodiments, the solid tumor is a sarcoma or carcinoma. In someembodiments, the solid tumor is a sarcoma. In some embodiments, thesolid tumor is a carcinoma. In some embodiments, the sarcoma is selectedfrom alveolar rhabdomyosarcoma; alveolar soft part sarcoma;ameloblastoma; angiosarcoma; chondrosarcoma; chordoma; clear cellsarcoma of soft tissue; dedifferentiated liposarcoma; desmoid;desmoplastic small round cell tumor; embryonal rhabdomyosarcoma;epithelioid fibrosarcoma; epithelioid hemangioendothelioma; epithelioidsarcoma; esthesioneuroblastoma; Ewing sarcoma; extrarenal rhabdoidtumor; extraskeletal myxoid chondrosarcoma; extrasketetal osteosarcoma;fibrosarcoma; giant cell tumor; hemangiopericytoma; infantilefibrosarcoma; inflammatory myofibroblastic tumor; Kaposi sarcoma;leiomyosarcoma of bone; liposarcoma; liposarcoma of bone; malignantfibrous histiocytoma (MFH); malignant fibrous histiocytoma (MFH) ofbone; malignant mesenchymoma; malignant peripheral nerve sheath tumor;mesenchymal chondrosarcoma; myxofibrosarcoma; myxoid liposarcoma;myxoinflammatory fibroblastic sarcoma; neoplasms with perivascularepitheioid cell differentiation; osteosarcoma; parosteal osteosarcoma;neoplasm with perivascular epitheioid cell differentiation; periostealosteosarcoma; pleomorphic liposarcoma; pleomorphic rhabdomyosarcoma;PNET/extraskeletal Ewing tumor; rhabdomyosarcoma; round cellliposarcoma; small cell osteosarcoma; solitary fibrous tumor; synovialsarcoma; telangiectatic osteosarcoma. In some embodiments, the carcinomais selected from an adenocarcinoma, squamous cell carcinoma,adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, orsmall cell carcinoma. In some embodiments, the carcinoma is selectedfrom anal cancer; appendix cancer; bile duct cancer (i.e.,cholangiocarcinoma); bladder cancer; brain tumor; breast cancer;cervical cancer; colon cancer; cancer of Unknown Primary (CUP);esophageal cancer; eye cancer; fallopian tube cancer; kidney cancer;liver cancer; lung cancer; medulloblastoma; melanoma; oral cancer;ovarian cancer; pancreatic cancer; parathyroid disease; penile cancer;pituitary tumor; prostate cancer; rectal cancer; skin cancer; stomachcancer; testicular cancer; throat cancer; thyroid cancer; uterinecancer; vaginal cancer; or vulvar cancer. In some embodiments, thecarcinoma is breast cancer. In some embodiments, the breast cancer isinvasive ductal carcinoma, ductal carcinoma in situ, invasive lobularcarcinoma, or lobular carcinoma in situ. In some embodiments, thecarcinoma is pancreatic cancer. In some embodiments, the pancreaticcancer is adenocarcinoma, or islet cell carcinoma. In some embodiments,the carcinoma is colorectal cancer. In some embodiments, the colorectalcancer is adenocarcinoma. In some embodiments, the solid tumor is acolon polyp. In some embodiments, the colon polyp is associated withfamilial adenomatous polyposis. In some embodiments, the carcinoma isbladder cancer. In some embodiments, the bladder cancer is transitionalcell bladder cancer, squamous cell bladder cancer, or adenocarcinoma. Insome embodiments, the carcinoma is lung cancer. In some embodiments, thelung cancer is a non-small cell lung cancer. In some embodiments, thenon-small cell lung cancer is adenocarcinoma, squamous-cell lungcarcinoma, or large-cell lung carcinoma. In some embodiments, the lungcancer is a small cell lung cancer. In some embodiments, the carcinomais prostate cancer. In some embodiments, the prostate cancer isadenocarcinoma or small cell carcinoma. In some embodiments, thecarcinoma is ovarian cancer. In some embodiments, the ovarian cancer isepithelial ovarian cancer. In some embodiments, the carcinoma is bileduct cancer. In some embodiments, the bile duct cancer is proximal bileduct carcinoma or distal bile duct carcinoma. In some embodiments,co-administration of ibrutinib and abexinostat is 5%, 10%, 15%, 20%,25%, 30%, 35%, 40%, 45%, 50%, 55% or 60% more efficacious thanadministration of abexinostat alone. In some embodiments,co-administration of the ibrutinib and abexinostat is 50% moreefficacious than administration of abexinostat alone. In someembodiments, co-administration of ibrutinib and abexinostat is 5%, 10%,15%, 20%, 25%, 30%, or 35% more efficacious than administration ofibrutinib alone. In some embodiments, co-administration of ibrutinib andabexinostat is 25% more efficacious than administration of ibrutinibalone. In some embodiments, abexinostat and ibrutinib are administeredin a unified dosage form or separate dosage forms. In some embodiments,abexinostat and ibrutinib are administered simultaneously orsequentially.

Disclosed herein, in certain embodiments, are compositions comprising atherapeutically effective amount of an ACK inhibitor compound, atherapeutically effective amount of an HDAC inhibitor compound, and apharmaceutically acceptable excipient. In some embodiments, the ACKinhibitor compound is a BTK inhibitor. In some embodiments, the BTKinhibitor is an irreversible BTK inhibitor. In some embodiments, the ACKinhibitor is a compound of Formula (A):

whereinA is independently selected from N or CR₅;R₁ is H, L₂-(substituted or unsubstituted alkyl), L₂-(substituted orunsubstituted cycloalkyl), L₂-(substituted or unsubstituted alkenyl),L₂-(substituted or unsubstituted cycloalkenyl), L₂-(substituted orunsubstituted heterocycle), L₂-(substituted or unsubstitutedheteroaryl), or L₂-(substituted or unsubstituted aryl), where L₂ is abond, O, S, —S(═O), —S(═O)₂, C(═O), -(substituted or unsubstituted C₁-C₆alkyl), or -(substituted or unsubstituted C₂-C₆ alkenyl);R₂ and R₃ are independently selected from H, lower alkyl and substitutedlower alkyl;R₄ is L₃-X-L₄-G, wherein,L₃ is optional, and when present is a bond, optionally substituted orunsubstituted alkyl, optionally substituted or unsubstituted cycloalkyl,optionally substituted or unsubstituted alkenyl, optionally substitutedor unsubstituted alkynyl;X is optional, and when present is a bond, O, —C(═O), S, —S(═O),—S(═O)₂, —NH, —NR₉, —NHC(O), —C(O)NH, —NR₉C(O), —C(O)NR₉, —S(═O)₂NH,—NHS(═O)₂, —S(═O)₂NR₉—, —NR₉S(═O)₂, —OC(O)NH—, —NHC(O)O—, —OC(O)NR₉—,—NR₉C(O)O—, —CH═NO—, —ON═CH—, —NR₁₀C(O)NR₁₀—, heteroaryl, aryl,—NR₁₀C(═NR₁)NR₁₀—, —NR₁₀C(═NR₁₁)—, —C(═NR₁₁)NR₁₀—, —OC(═NR₁₁)—, or—C(═NR₁₁)O—;L₄ is optional, and when present is a bond, substituted or unsubstitutedalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted heterocycle;or L₃, X and L₄ taken together form a nitrogen containing heterocyclicring;G is

wherein,R₆, R₇ and R₈ are independently selected from among H, lower alkyl orsubstituted lower alkyl, lower heteroalkyl or substituted lowerheteroalkyl, substituted or unsubstituted lower cycloalkyl, andsubstituted or unsubstituted lower heterocycloalkyl;R₅ is H, halogen, -L₆-(substituted or unsubstituted C₁-C₃ alkyl),-L₆-(substituted or unsubstituted C₂-C₄ alkenyl), -L₆-(substituted orunsubstituted heteroaryl), or -L₆-(substituted or unsubstituted aryl),wherein L₆ is a bond, O, S, —S(═O), S(═O)₂, NH, C(O), —NHC(O)O,—OC(O)NH, —NHC(O), or —C(O)NH;each R₉ is independently selected from among H, substituted orunsubstituted lower alkyl, and substituted or unsubstituted lowercycloalkyl;each R₁₀ is independently H, substituted or unsubstituted lower alkyl,or substituted or unsubstituted lower cycloalkyl; ortwo R₁₀ groups can together form a 5-, 6-, 7-, or 8-memberedheterocyclic ring; orR₉ and R₁₀ can together form a 5-, 6-, 7-, or 8-membered heterocyclicring; oreach R₁₁ is independently selected from H, —S(═O)₂R₈, —S(═O)₂NH₂,—C(O)R₈, —CN, —NO₂, heteroaryl, or heteroalkyl. In some embodiments, theACK inhibitor is(R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one(i.e. PCI-32765/ibrutinib)

In some embodiments, the ACK inhibitor is AVL-263 (AvilaTherapeutics/Celgene Corporation), AVL-292 (Avila Therapeutics/CelgeneCorporation), AVL-291 (Avila Therapeutics/Celgene Corporation),BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb),CGI-1746 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech),HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21,HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co.,Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (PekingUniversity), RN486 (Hoffmann-La Roche), or HM71224 (Hanmi PharmaceuticalCompany Limited). In some embodiments, the HDAC inhibitor is a compoundof Formula (B):

wherein:R¹ is hydrogen or alkyl;X is —O—, —NR²—, or —S(O)_(n) where n is 0-2 and R² is hydrogen oralkyl;Y is alkylene optionally substituted with cycloalkyl, optionallysubstituted phenyl, alkylthio, alkylsulfinyl, alkysulfonyl, optionallysubstituted phenylalkylthio, optionally substituted phenylalkylsulfonyl,hydroxy, or optionally substituted phenoxy;Ar¹ is phenylene or heteroarylene wherein said Ar¹ is optionallysubstituted with one or two groups independently selected from alkyl,halo, hydroxy, alkoxy, haloalkoxy, or haloalkyl;R³ is hydrogen, alkyl, hydroxyalkyl, or optionally substituted phenyl;andAr² is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl,heteroaralkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, orheterocycloalkylalkyl. In some embodiments, the HDAC inhibitor is3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide(i.e. PCI-24781/abexinostat)

In some embodiments, the HDAC inhibitor is3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide(i.e. PCI-24781/abexinostat)

and, the ACK inhibitor is(R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one(i.e. PCI-32765/ibrutinib)

In some embodiments, the composition is in the form of a solid dosageform. In some embodiments, the composition is in the form of a capsule.In some embodiments, the composition is in the form of a solution. Insome embodiments, the composition is in the form of a solution forintravenous administration. In some embodiments, the compositioncomprises 140 mg of ibrutinib.

Other objects, features and advantages of the methods and compositionsdescribed herein will become apparent from the following detaileddescription. It should be understood, however, that the detaileddescription and the specific examples, while indicating specificembodiments, are given by way of illustration only. The section headingsused herein are for organizational purposes only and are not to beconstrued as limiting the subject matter described.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1: Is an illustrative example of the average number of tumors onthe lung surface for control and drug-treated (abexinostat, ibrutinib,or abexinostat+ibrutinib) Grg1 transgenic mice. The bars at the leftshow mice treated for 4 weeks beginning at 2 months (3 month samples)and the bars in the middle show mice treated for 4 weeks beginning at 5months (6 month samples). The average number of tumors over 1 mm for 6month samples is also shown.

FIG. 2: Is an illustrative example of the number of surface tumors perGrg1 transgenic mice at 3 months after 4 weeks of treatment withabexinostat, ibrutinib, or the combination of abexinostat and ibrutinib.

FIG. 3: Is an illustrative example of tumor sections from Grg1transgenic mice at 3 months. Tumor sections from control mice (A, B),Abexinostat-treated mice (C, D), and Ibrutinib-treated mice (E, F).Arrows in A, C, E point to tumors. Original magnification of images inthe left column was 50× and in the right column was 400×.

FIG. 4: Is an illustrative example of the number of surface tumors perGrg1 transgenic mice at 6 months after 4 weeks of treatment withabexinostat, ibrutinib, or the combination of abexinostat and ibrutinib.

FIG. 5: Is an illustrative example of tumor diameter in tissue sectionsat 6 months for Grg1 transgenic mice after 4 weeks of treatment withabexinostat, ibrutinib, or the combination of abexinostat and ibrutinib.Each column represents one mouse sample, and the size of each tumorpresent in the sectioned slides for that mouse sample is given in thecolumn. Each bar in the graph represents the diameter of one tumor andeach group of bars represents one mouse. Four mice were analyzed fromthe control group, and two mice were analyzed for each of thedrug-treated groups.

FIG. 6: Is an illustrative example of the number of tumors over 1 mm in6 month samples from Grg1 transgenic mice after 4 weeks of treatmentwith abexinostat, ibrutinib, or the combination of abexinostat andibrutinib. Each number in the table and bar in the graph represents thenumber of tumors>1 mm for one mouse. The average number of large tumorsper mouse for each treatment group is shown in the bottom row of thetable and the right-most bar for each group.

FIG. 7: Is an illustrative example of whole left lung lobes from 6 monthGrg1 transgenic mice after 4 weeks of treatment with abexinostat,ibrutinib, or the combination of abexinostat and ibrutinib. Three largetumors and one small tumor are visible in the control sample (A); mediumand small tumors are visible in Abexinostat-treated (B),Ibrutinib-treated (C) and Abexinostat+Ibrutinib-treated (D) samples.

FIG. 8: Is an illustrative example of whole lung lobes from 3 month Grg1transgenic mice after 4 weeks of treatment with abexinostat, ibrutinib,or the combination of abexinostat and ibrutinib. Four large tumors arevisible in the control sample (A); one small tumor is visible inAbexinostat-treated (B) and Ibrutinib-treated (C) samples, and novisible tumors are seen in the Abexinostat+Ibrutinib-treated (D)samples.

FIG. 9: Is a table exemplifying the effects on tumor diameter in 6 monthsections of the combination of abexinostat and ibrutinib. The first baris the control. The second bar shows the results following treatmentwith abexinostat alone. The third bar shows the results followingtreatment with ibrutinib alone. The fourth bar shows the resultsfollowing treatment with abexinostat and ibrutinib. There were manylarge tumors in controls compared to treated groups. Interestingly,there were no small tumors in Ib-treated sections, just one large tumor.

FIG. 10: Is an illustrative example of lung tissue sections from 6 monthGrg1 transgenic mice after 4 weeks of treatment with abexinostat,ibrutinib, or the combination of abexinostat and ibrutinib. In thetissue sections, tumors in control mice exhibit lymphocyte infiltration(L), necrosis (N) and a high number of apoptotic macrophages (FIGS. 8Aand B). Tumors from Abexinostat-treated mice have lymphocyteinfiltration, necrosis and large areas with apoptotic cells (FIGS. 8Cand 8D). Tumors from Ibrutinib-treated mice have lymphocyte infiltrationbut not the apoptotic macrophages seen in the control and inAbexinostat-treated mice (FIGS. 8E and 8F). Tumors fromAbexinostat+Ibrutinib-treated mice have lymphocyte infiltration andmacrophage present but not a high number of apoptotic macrophage (FIGS.8G and 8H).

FIG. 11: Is a table exemplifying the effects of the combination ofabexinostat and ibrutinib is MDA-MB-453 cells (breast carcinoma), DLD-1cells (colorectal adenocarcinoma), NCI-H460 cells (large cell lungcancer), A549 cells (lung carcinoma) and LNCap cells (prostatecarcinoma). The combination showed synergy for MDA-MB-453 cells, weaksynergy for DLD-1 cells, additivity for NCI-H460 cells, and noadditional effect for A549 and LNCaP cells.

FIG. 12: Is an illustrative example of the effects of the combination ofabexinostat and ibrutinib in MDA-MB-453 cells (breast carcinoma). 24781is abexinostat and 32765 is ibrutinib. CI value<1 indicates synergy, CIvalue=1 indicates additive, and CI value>1 indicate antagonist.

FIG. 13: Is an illustrative example of the effects of the combination ofabexinostat and ibrutinib in DLD-1 cells (colorectal adenocarcinoma).24781 is abexinostat and 32765 is ibrutinib. CI value<1 indicatessynergy, CI value=1 indicates additive, and CI value>1 indicateantagonist.

FIG. 14: Is an illustrative example of the effects of the combination ofabexinostat and ibrutinib in NCI-H460 cells (large cell lung cancer).24781 is abexinostat and 32765 is ibrutinib. CI value<1 indicatessynergy, CI value=1 indicates additive, and CI value>1 indicateantagonist.

FIG. 15: Is an illustrative example of the effects of the combination ofabexinostat and ibrutinib in A549 cells (lung carcinoma). 24781 isabexinostat and 32765 is ibrutinib.

FIG. 16: Is an illustrative example of the effects of the combination ofabexinostat and ibrutinib in LNCaP cells (prostate carcinoma). 24781 isabexinostat and 32765 is ibrutinib.

DETAILED DESCRIPTION OF THE INVENTION

Described herein methods of treating solid tumors comprisingco-administering an ACK inhibitor compound (e.g., a BTK inhibitor, suchas for example an irreversible BTK inhibitor, such as for exampleibrutinib) and an HDAC inhibitor compound. In some embodiments, the ACKinhibitor compound (e.g., a BTK inhibitor, such as for example anirreversible BTK inhibitor, such as for example ibrutinib) is a compoundof Formula (A). In some embodiments, the ACK inhibitor compound is(R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one(i.e. PCI-32765/ibrutinib).

In some embodiments, the ACK inhibitor is AVL-263 (AvilaTherapeutics/Celgene Corporation), AVL-292 (Avila Therapeutics/CelgeneCorporation), AVL-291 (Avila Therapeutics/Celgene Corporation),BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb),CGI-1746 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech),HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21,HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co.,Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (PekingUniversity), RN486 (Hoffmann-La Roche), or HM71224 (Hanmi PharmaceuticalCompany Limited). In some embodiments, the HDAC inhibitor is a compoundof Formula (B). In some embodiments, the HDAC inhibitor is3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide(i.e. PCI-24781/abexinostat).

Certain Terminology

It is to be understood that the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of any subject matter claimed. In this application,the use of the singular includes the plural unless specifically statedotherwise. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. In thisapplication, the use of “or” means “and/or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as“include”, “includes,” and “included,” is not limiting.

As used herein, “ACK” and “Accessible Cysteine Kinase” are synonyms.They mean a kinase with an accessible cysteine residue. ACKs include,but are not limited to, BTK, ITK, Bmx/ETK, TEC, EFGR, HER4, HER4, LCK,BLK, C-src, FGR, Fyn, HCK, Lyn, YES, ABL, Brk, CSK, FER, JAK3, SYK. Insome embodiments, the ACK is HER4.

As used herein, “amelioration” refers to any lessening of severity,delay in onset, slowing of growth, slowing of metastasis, or shorteningof duration of a solid tumor, whether permanent or temporary, lasting ortransient that can be attributed to or associated with administration ofthe compound or composition.

The term “Bruton's tyrosine kinase,” as used herein, refers to Bruton'styrosine kinase from Homo sapiens, as disclosed in, e.g., U.S. Pat. No.6,326,469 (GenBank Accession No. NP_000052).

The term “Bruton's tyrosine kinase homolog,” as used herein, refers toorthologs of Bruton's tyrosine kinase, e.g., the orthologs from mouse(GenBank Accession No. AAB47246), dog (GenBank Accession No. XP_549139),rat (GenBank Accession No. NP_001007799), chicken (GenBank Accession No.NP_989564), or zebra fish (GenBank Accession No. XP_698117), and fusionproteins of any of the foregoing that exhibit kinase activity towardsone or more substrates of Bruton's tyrosine kinase (e.g. a peptidesubstrate having the amino acid sequence “AVLESEEELYSSARQ”).

The term “HER4”, also known as ERBB4, also known as “V-erb-aerythroblastic leukemia viral oncogene homolog 4” means either (a) thenucleic acid sequence encoding a receptor tyrosine kinase that is amember of the epidermal growth factor receptor subfamily, or (b) theprotein thereof. For the nucleic acid sequence that comprises the humanHER4 gene see GenBank Accession No. NM_001042599. For the amino acidsequence that comprises the human HER4 protein see GenBank Accession No.NP_001036064.

The terms “co-administration” or the like, as used herein, encompassadministration of an ACK inhibitor compound and an HDAC inhibitorcompound to a single patient, and are intended to include treatmentregimens in which the agents are administered by the same or differentroute of administration, in the same or a different dosage form, and atthe same or different time.

The term “homologous cysteine,” as used herein refers to a cysteineresidue found within a sequence position that is homologous to that ofcysteine 481 of Bruton's tyrosine kinase, as defined herein. Forexample, cysteine 482 is the homologous cysteine of the rat ortholog ofBruton's tyrosine kinase; cysteine 479 is the homologous cysteine of thechicken ortholog; and cysteine 481 is the homologous cysteine in thezebra fish ortholog. In another example, the homologous cysteine of TXK,a Tec kinase family member related to Bruton's tyrosine, is Cys 350.

The term “irreversible Btk inhibitor,” as used herein, refers to aninhibitor of Btk that can form a covalent bond with an amino acidresidue of Btk. In one embodiment, the irreversible inhibitor of Btk canform a covalent bond with a Cys residue of Btk; in particularembodiments, the irreversible inhibitor can form a covalent bond with aCys 481 residue (or a homolog thereof) of Btk or a cysteine residue inthe homologous corresponding position of another tyrosine kinase, asshown in FIG. 7.

As used herein, the term “pERK” refers to phosphorylated ERK1 and ERK2at Thr202/Tyr 204 as detected by commercially available phospho-specificantibodies (e.g. Cell Signaling Technologies #4377).

The terms “individual”, “patient” and “subject” are usedinterchangeable. They refer to a mammal (e.g., a human) which is theobject of treatment, or observation. The term is not to be construed asrequiring the supervision of a medical practitioner (e.g., a physician,physician's assistant, nurse, orderly, hospice care worker).

The terms “treat,” “treating” or “treatment”, as used herein, includelessening of severity of a solid tumor, delay in onset of a solid tumor,slowing the growth of a solid tumor, slowing metastasis of cells of asolid tumor, shortening of duration of a solid tumor, arresting thedevelopment of a solid tumor, causing regression of a solid tumor,relieving a condition caused by of a solid tumor, or stopping symptomswhich result from a solid tumor. The terms “treat,” “treating” or“treatment”, include, but are not limited to, prophylactic and/ortherapeutic treatments.

Therapeutic Methods

Described herein methods of treating solid tumors comprisingco-administering an ACK inhibitor compound (e.g., a BTK inhibitor, suchas for example an irreversible BTK inhibitor, such as for exampleibrutinib) and an HDAC inhibitor compound. In some embodiments, the ACKinhibitor compound (e.g., a BTK inhibitor, such as for example anirreversible BTK inhibitor, such as for example ibrutinib) is a compoundof Formula (A). In some embodiments, the ACK inhibitor compound is(R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one(i.e. PCI-32765/ibrutinib). In some embodiments, the ACK inhibitor isAVL-263 (Avila Therapeutics/Celgene Corporation), AVL-292 (AvilaTherapeutics/Celgene Corporation), AVL-291 (Avila Therapeutics/CelgeneCorporation), BMS-488516 (Bristol-Myers Squibb), BMS-509744(Bristol-Myers Squibb), CGI-1746 (CGI Pharma/Gilead Sciences), CTA-056,GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22,HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (OnoPharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.),PLS-123 (Peking University), RN486 (Hoffmann-La Roche), or HM71224(Hanmi Pharmaceutical Company Limited). In some embodiments, the HDACinhibitor is a compound of Formula (B). In some embodiments, the HDACinhibitor is3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide(i.e. PCI-24781/abexinostat).

Solid Tumors

As used herein, a “solid tumor” is an abnormal mass of tissue resultingfrom the abnormal growth or division of cells (i.e., neoplasia). Solidtumors are characterized by an absence of liquid areas. In someembodiments, the solid tumor is benign. In some embodiments, the solidtumor is malignant (i.e., a cancer).

In some embodiments, the solid tumor is a sarcoma, or carcinoma.

In some embodiments, the solid tumor is a sarcoma. Sarcomas are cancersof the bone, cartilage, fat, muscle, blood vessels, or other connectiveor supportive tissue. Sarcomas include, but are not limited to, alveolarrhabdomyosarcoma; alveolar soft part sarcoma; ameloblastoma;angiosarcoma; chondrosarcoma; chordoma; clear cell sarcoma of softtissue; dedifferentiated liposarcoma; desmoid; desmoplastic small roundcell tumor; embryonal rhabdomyosarcoma; epithelioid fibrosarcoma;epithelioid hemangioendothelioma; epithelioid sarcoma;esthesioneuroblastoma; Ewing sarcoma; extrarenal rhabdoid tumor;extraskeletal myxoid chondrosarcoma; extrasketetal osteosarcoma;fibrosarcoma; giant cell tumor; hemangiopericytoma; infantilefibrosarcoma; inflammatory myofibroblastic tumor; Kaposi sarcoma;leiomyosarcoma of bone; liposarcoma; liposarcoma of bone; malignantfibrous histiocytoma (MFH); malignant fibrous histiocytoma (MFH) ofbone; malignant mesenchymoma; malignant peripheral nerve sheath tumor;mesenchymal chondrosarcoma; myxofibrosarcoma; myxoid liposarcoma;myxoinflammatory fibroblastic sarcoma; neoplasms with perivascularepitheioid cell differentiation; osteosarcoma; parosteal osteosarcoma;neoplasm with perivascular epitheioid cell differentiation; periostealosteosarcoma; pleomorphic liposarcoma; pleomorphic rhabdomyosarcoma;PNET/extraskeletal Ewing tumor; rhabdomyosarcoma; round cellliposarcoma; small cell osteosarcoma; solitary fibrous tumor; synovialsarcoma; telangiectatic osteosarcoma.

In some embodiments, the solid tumor is a carcinoma. Carcinomas arecancers that begin in the epithelial cells. Carcinomas are classified asadenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma,anaplastic carcinoma, large cell carcinoma, small cell carcinoma. By wayof non-limiting example, carcinomas include, anal cancer; appendixcancer; bile duct cancer (i.e., cholangiocarcinoma); bladder cancer;brain tumor; breast cancer; cervical cancer; colon cancer; cancer ofUnknown Primary (CUP); esophageal cancer; eye cancer; fallopian tubecancer; kidney cancer; liver cancer; lung cancer; medulloblastoma;melanoma; oral cancer; ovarian cancer; pancreatic cancer; parathyroiddisease; penile cancer; pituitary tumor; prostate cancer; rectal cancer;skin cancer (e.g., basal cell carcinoma, squamous cell carcinoma,malignant melanoma); stomach cancer; testicular cancer; throat cancer;thyroid cancer; uterine cancer; vaginal cancer; or vulvar cancer.

In some embodiments, the solid tumor is breast cancer. In someembodiments, the breast cancer is invasive ductal carcinoma (e.g.,triple-negative breast cancer), ductal carcinoma in situ, invasivelobular carcinoma, or lobular carcinoma in situ.

In some embodiments, the solid tumor is pancreatic cancer. In someembodiments, the pancreatic cancer is adenocarcinoma, or islet cellcarcinoma.

In some embodiments, the solid tumor is colorectal cancer. In someembodiments, the colorectal cancer is adenocarcinoma. In someembodiments, the solid tumor is a colon polyp, for example associatedwith familial adenomatous polyposis.

In some embodiments, the solid tumor is bladder cancer. In someembodiments, the bladder cancer is transitional cell bladder cancer,squamous cell bladder cancer, or adenocarcinoma.

In some embodiments, the solid tumor is lung cancer. In someembodiments, the lung cancer is a non-small cell lung cancer. In someembodiments, the lung cancer is a small cell lung cancer. In someembodiments, the non-small cell lung cancer is adenocarcinoma,squamous-cell lung carcinoma, or large-cell lung carcinoma. In someembodiments, the lung cancer is large cell lung cancer.

In some embodiments, the solid tumor is prostate cancer. In someembodiments, the prostate cancer is adenocarcinoma or small cellcarcinoma.

In some embodiments, the solid tumor is ovarian cancer (e.g., epithelialovarian cancer).

In some embodiments, the solid tumor is bile duct cancer. In someembodiments, the bile duct cancer is proximal bile duct carcinoma ordistal bile duct carcinoma.

Synergistic Effects

Described herein methods of treating solid tumors comprisingco-administering an ACK inhibitor compound (e.g., a BTK inhibitor, suchas for example an irreversible BTK inhibitor, such as for exampleibrutinib) and an HDAC inhibitor compound. In some embodiments, the ACKinhibitor compound (e.g., a BTK inhibitor, such as for example anirreversible BTK inhibitor, such as for example ibrutinib) is a compoundof Formula (A). In some embodiments, the ACK inhibitor compound is(R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one(i.e. PCI-32765/ibrutinib). In some embodiments, the ACK inhibitor isAVL-263 (Avila Therapeutics/Celgene Corporation), AVL-292 (AvilaTherapeutics/Celgene Corporation), AVL-291 (Avila Therapeutics/CelgeneCorporation), BMS-488516 (Bristol-Myers Squibb), BMS-509744(Bristol-Myers Squibb), CGI-1746 (CGI Pharma/Gilead Sciences), CTA-056,GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22,HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (OnoPharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.),PLS-123 (Peking University), RN486 (Hoffmann-La Roche), or HM71224(Hanmi Pharmaceutical Company Limited). In some embodiments, the HDACinhibitor is a compound of Formula (B). In some embodiments, the HDACinhibitor is3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide(i.e. PCI-24781/abexinostat).

In some embodiments, the co-administration of and ACK inhibitor (e.g.,ibrutinib) and an HDAC inhibitor (e.g., abexinostat) results in asynergistic effect for the treatment of a solid tumor (e.g., reductionin the number of tumors, growth/size of tumors, metastasis of tumors)

In some embodiments, co-administration of an ACK inhibitor (e.g.,ibrutinib) and an HDAC inhibitor (e.g., abexinostat) is 5%, 10%, 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or 60% more efficacious thanadministration of an HDAC inhibitor (e.g., abexinostat) alone. In someembodiments, co-administration of an ACK inhibitor (e.g., ibrutinib) andan HDAC inhibitor (e.g., abexinostat) is 50% more efficacious thanadministration of an HDAC inhibitor (e.g., abexinostat) alone. In someembodiments, co-administration of an ACK inhibitor (e.g., ibrutinib) andan HDAC inhibitor (e.g., abexinostat) is 1.1×, 1.2×, 1.3×, 1.4×, 1.5×,or 1.6× more efficacious than administration of an HDAC inhibitor (e.g.,abexinostat) alone. In some embodiments, co-administration of an ACKinhibitor (e.g., ibrutinib) and an HDAC inhibitor (e.g., abexinostat) is1.5× more efficacious than administration of an HDAC inhibitor (e.g.,abexinostat) alone.

In some embodiments, co-administration of an ACK inhibitor (e.g.,ibrutinib) and an HDAC inhibitor (e.g., abexinostat) is 5%, 10%, 15%,20%, 25%, 30%, or 35% more efficacious than administration of an ACKinhibitor (e.g., ibrutinib) alone. In some embodiments,co-administration of an ACK inhibitor (e.g., ibrutinib) and an HDACinhibitor (e.g., abexinostat) is 25% more efficacious thanadministration of an ACK inhibitor (e.g., ibrutinib) alone. In someembodiments, co-administration of an ACK inhibitor (e.g., ibrutinib) andan HDAC inhibitor (e.g., abexinostat) is 1.1×, 1.15×, 1.2×, 1.25×, or1.3× more efficacious than administration of an ACK inhibitor (e.g.,ibrutinib) alone. In some embodiments, co-administration of an ACKinhibitor (e.g., ibrutinib) and an HDAC inhibitor (e.g., abexinostat) is1.25× more efficacious than administration of an ACK inhibitor (e.g.,ibrutinib) alone.

In some embodiments, co-administration of ibrutinib and abexinostat is5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or 60% moreefficacious than administration of abexinostat alone. In someembodiments, co-administration of ibrutinib and abexinostat is 50% moreefficacious than administration of abexinostat alone. In someembodiments, co-administration of ibrutinib and abexinostat is 1.1×,1.2×, 1.3×, 1.4×, 1.5×, or 1.6× more efficacious than administration ofabexinostat alone. In some embodiments, co-administration of ibrutiniband abexinostat is 1.5× more efficacious than administration ofabexinostat alone.

In some embodiments, co-administration of ibrutinib and abexinostat is5%, 10%, 15%, 20%, 25%, 30%, or 35% more efficacious than administrationof ibrutinib alone. In some embodiments, co-administration of ibrutiniband abexinostat is 25% more efficacious than administration of ibrutinibalone. In some embodiments, co-administration of ibrutinib andabexinostat is 1.1×, 1.15×, 1.2×, 1.25×, or 1.3× more efficacious thanadministration of ibrutinib alone. In some embodiments,co-administration of ibrutinib and abexinostat is 1.25× more efficaciousthan administration of ibrutinib alone.

Administration

Described herein methods of treating solid tumors comprisingco-administering an ACK inhibitor compound (e.g., a BTK inhibitor, suchas for example an irreversible BTK inhibitor, such as for exampleibrutinib) and an HDAC inhibitor compound. In some embodiments, the ACKinhibitor compound (e.g., a BTK inhibitor, such as for example anirreversible BTK inhibitor, such as for example ibrutinib) is a compoundof Formula (A). In some embodiments, the ACK inhibitor compound is(R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one(i.e. PCI-32765/ibrutinib). In some embodiments, the ACK inhibitor isAVL-263 (Avila Therapeutics/Celgene Corporation), AVL-292 (AvilaTherapeutics/Celgene Corporation), AVL-291 (Avila Therapeutics/CelgeneCorporation), BMS-488516 (Bristol-Myers Squibb), BMS-509744(Bristol-Myers Squibb), CGI-1746 (CGI Pharma/Gilead Sciences), CTA-056,GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22,HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (OnoPharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.),PLS-123 (Peking University), RN486 (Hoffmann-La Roche), or HM71224(Hanmi Pharmaceutical Company Limited). In some embodiments, the HDACinhibitor is a compound of Formula (B). In some embodiments, the HDACinhibitor is3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide(i.e. PCI-24781/abexinostat).

In some embodiments, the ACK inhibitor compound (e.g., a BTK inhibitor,such as for example, an irreversible BTK inhibitor, such as for example,ibrutinib) and the HDAC inhibitor are administered in the samecomposition. In some embodiments, the ACK inhibitor compound (e.g., aBTK inhibitor, such as for example an irreversible BTK inhibitor, suchas for example ibrutinib) and the HDAC inhibitor are not administered inthe same composition. In some embodiments, the ACK inhibitor compound(e.g., a BTK inhibitor, such as for example an irreversible BTKinhibitor, such as for example ibrutinib) and the HDAC inhibitor areadministered by different routes. In some embodiments, the ACK inhibitorcompound (e.g., a BTK inhibitor, such as for example an irreversible BTKinhibitor, such as for example ibrutinib) and the HDAC inhibitor areadministered simultaneously or sequentially.

If simultaneously, the multiple therapeutic agents are optionallyprovided in a single, unified form, or in multiple forms (by way ofexample only, either as a single pill or as two separate pills). In someembodiments, one of therapeutic agents is given in multiple doses, orboth are given as multiple doses. If not simultaneous, the timingbetween the multiple doses is from about more than zero weeks to lessthan about four weeks.

In some embodiments, the ACK inhibitor compound (e.g., a BTK inhibitor,such as for example an irreversible BTK inhibitor, such as for exampleibrutinib) and the HDAC inhibitor are administered in a combined dosageform, or in separate dosage forms intended for substantiallysimultaneous administration. In some embodiments, the ACK inhibitorcompound (e.g., a BTK inhibitor, such as for example an irreversible BTKinhibitor, such as for example ibrutinib) and the HDAC inhibitor areadministered sequentially, with either therapeutic compound beingadministered by a regimen calling for two-step administration. In someembodiments, the two-step administration regimen calls for sequentialadministration of the active agents or spaced-apart administration ofthe separate active agents. The time period between the multipleadministration steps ranges from a few minutes to several hours,depending upon the properties of each pharmaceutical agent, such aspotency, solubility, bioavailability, plasma half-life and kineticprofile of the pharmaceutical agent. In some embodiments, circadianvariation of the target molecule concentration determines the optimaldose interval.

The ACK inhibitor compound (e.g., a BTK inhibitor, such as for examplean irreversible BTK inhibitor, such as for example ibrutinib) and theHDAC inhibitor compounds described herein are administered before,during or after the development of a solid tumor. In some embodiments,the ACK inhibitor compound (e.g., a BTK inhibitor, such as for examplean irreversible BTK inhibitor, such as for example ibrutinib) and theHDAC inhibitor compounds are used as a prophylactic and are administeredcontinuously to subjects with a propensity to develop a solid tumor. Insome embodiments, the ACK inhibitor compound (e.g., a BTK inhibitor,such as for example an irreversible BTK inhibitor, such as for exampleibrutinib) and the HDAC inhibitor compounds are administered to anindividual during or as soon as possible after the development of asolid tumor. In some embodiments, the administration of the ACKinhibitor compound (e.g., a BTK inhibitor, such as for example anirreversible BTK inhibitor, such as for example ibrutinib) and the HDACinhibitor compounds is initiated within the first 48 hours of the onsetof the symptoms, within the first 6 hours of the onset of the symptoms,or within 3 hours of the onset of the symptoms. In some embodiments, theinitial administration of the ACK inhibitor compound (e.g., a BTKinhibitor, such as for example an irreversible BTK inhibitor, such asfor example ibrutinib) and the HDAC inhibitor compounds is via any routepractical, such as, for example, an intravenous injection, a bolusinjection, infusion over 5 minutes to about 5 hours, a pill, a capsule,transdermal patch, buccal delivery, and the like, or combinationthereof. The ACK inhibitor compound (e.g., a BTK inhibitor, such as forexample an irreversible BTK inhibitor, such as for example ibrutinib)and the HDAC inhibitor compounds should be administered as soon as ispracticable after the onset of a disorder is detected or suspected, andfor a length of time necessary for the treatment of the disease, suchas, for example, from about 1 month to about 3 months. The length oftreatment can vary for each subject, and the length can be determinedusing the known criteria. In some embodiments, the ACK inhibitorcompound (e.g., a BTK inhibitor, such as for example an irreversible BTKinhibitor, such as for example ibrutinib) and the HDAC inhibitorcompounds are administered for at least 2 weeks, between about 1 monthto about 5 years, or from about 1 month to about 3 years.

Therapeutically effective amounts will depend on the severity and courseof the disorder, previous therapy, the patient's health status, weight,and response to the drugs, and the judgment of the treating physician.Prophalactically effective amounts depend on the patient's state ofhealth, weight, the severity and course of the disease, previoustherapy, response to the drugs, and the judgment of the treatingphysician.

In some embodiments, the ACK inhibitor compound (e.g., a BTK inhibitor,such as for example an irreversible BTK inhibitor, such as for exampleibrutinib) and HDAC inhibitor compounds are administered to the patienton a regular basis, e.g., three times a day, two times a day, once aday, every other day or every 3 days. In other embodiments, the ACKinhibitor compound (e.g., a BTK inhibitor, such as for example anirreversible BTK inhibitor, such as for example ibrutinib) ACK inhibitorcompound (e.g., a BTK inhibitor, such as for example an irreversible BTKinhibitor, such as for example ibrutinib) and HDAC inhibitor compoundsare administered to the patient on an intermittent basis, e.g., twice aday followed by once a day followed by three times a day; or the firsttwo days of every week; or the first, second and third day of a week. Insome embodiments, intermittent dosing is as effective as regular dosing.In further or alternative embodiments, the ACK inhibitor compound (e.g.,a BTK inhibitor, such as for example an irreversible BTK inhibitor, suchas for example ibrutinib) and HDAC inhibitor compounds are administeredonly when the patient exhibits a particular symptom, e.g., the onset ofpain, or the onset of a fever, or the onset of an inflammation, or theonset of a skin disorder. Dosing schedules of each compound may dependon the other or may be independent of the other.

In the case wherein the patient's condition does not improve, upon thedoctor's discretion the administration of the compounds may beadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisorder.

In the case wherein the patient's status does improve, upon the doctor'sdiscretion the administration of the compounds may be givencontinuously; alternatively, the dose of drug being administered may betemporarily reduced or temporarily suspended for a certain length oftime (i.e., a “drug holiday”). The length of the drug holiday can varybetween 2 days and 1 year, including by way of example only, 2 days, 3days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days,180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or365 days. The dose reduction during a drug holiday may be from 10%-100%,including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%,45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

Once improvement of the patient's conditions has occurred, a maintenanceregimen is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, of one or both of the ACKinhibitor compound (e.g., a BTK inhibitor, such as for example anirreversible BTK inhibitor, such as for example ibrutinib) and HDACinhibitor compounds can be reduced, as a function of the symptoms, to alevel at which the individual's improved condition is retained.Individuals can, however, require intermittent treatment on a long-termbasis upon any recurrence of symptoms.

The amount of the ACK inhibitor compound (e.g., a BTK inhibitor, such asfor example an irreversible BTK inhibitor, such as for exampleibrutinib) and HDAC inhibitor compounds will vary depending upon factorssuch as the particular compound, disorder and its severity, the identity(e.g., weight) of the subject or host in need of treatment, and isdetermined according to the particular circumstances surrounding thecase, including, e.g., the specific agents being administered, theroutes of administration, the solid tumor being treated, and the subjector host being treated. In general, however, doses employed for adulthuman treatment will typically be in the range of 0.02-5000 mg per day,or from about 1-1500 mg per day of each compound. The desired dose ofeach compound may be presented in a single dose or as divided dosesadministered simultaneously (or over a short period of time) or atappropriate intervals, for example as two, three, four or more sub-dosesper day.

In some embodiments, the amount of the ACK inhibitor (e.g., a BTKinhibitor, such as for example an irreversible BTK inhibitor, such asfor example ibrutinib) is from 300 mg/day up to, and including, 1000mg/day. In some embodiments, the amount of the irreversible Btkinhibitor is from 420 mg/day up to, and including, 840 mg/day. In someembodiments, the amount of the irreversible Btk inhibitor is about 420mg/day, about 560 mg/day, or about 840 mg/day. In some embodiments, theamount of the irreversible Btk inhibitor is about 420 mg/day.

In some embodiments, the HDAC inhibitor (e.g., abexinostat) isadministered for 4 consecutive days, followed by three consecutive dayswithout administration of the HDAC inhibitor (e.g., abexinostat).

The ACK inhibitor compound (e.g., a BTK inhibitor, such as for examplean irreversible BTK inhibitor, such as for example ibrutinib) and HDACinhibitor compounds described herein may be individually or combinedinto unit dosage forms suitable for single administration of precisedosages. In unit dosage form, the formulation is divided into unit dosescontaining appropriate quantities of one or both compounds. The unitdosage may be in the form of a package containing discrete quantities ofthe formulation. Non-limiting examples are packaged tablets or capsules,and powders in vials or ampoules. Aqueous suspension compositions can bepackaged in single-dose non-reclosable containers. Alternatively,multiple-dose reclosable containers can be used, in which case it istypical to include a preservative in the composition. By way of exampleonly, formulations for parenteral injection may be presented in unitdosage form, which include, but are not limited to ampoules, or inmulti-dose containers, with an added preservative.

It is understood that a medical professional will determine the dosageregimen in accordance with a variety of factors. These factors includethe solid tumor from which the subject suffers, the degree ofmetastasis, as well as the age, weight, sex, diet, and medical conditionof the subject.

Compounds

Described herein methods of treating solid tumors comprisingco-administering an ACK inhibitor compound (e.g., a BTK inhibitor, suchas for example an irreversible BTK inhibitor, such as for exampleibrutinib) and an HDAC inhibitor compound.

Definition of standard chemistry terms are found in reference works,including Carey and Sundberg “ADVANCED ORGANIC CHEMISTRY 4^(TH) ED.”Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwiseindicated, conventional methods of mass spectroscopy, NMR, HPLC, proteinchemistry, biochemistry, recombinant DNA techniques and pharmacology,within the skill of the art are employed. Unless specific definitionsare provided, the nomenclature employed in connection with, and thelaboratory procedures and techniques of, analytical chemistry, syntheticorganic chemistry, and medicinal and pharmaceutical chemistry describedherein are those known in the art. Standard techniques are optionallyused for chemical syntheses, chemical analyses, pharmaceuticalpreparation, formulation, and delivery, and treatment of patients.Standard techniques are optionally used for recombinant DNA,oligonucleotide synthesis, and tissue culture and transformation (e.g.,electroporation, lipofection). Reactions and purification techniques areperformed using documented methodologies or as described herein.

It is to be understood that the methods and compositions describedherein are not limited to the particular methodology, protocols, celllines, constructs, and reagents described herein and as such optionallyvary. It is also to be understood that the terminology used herein isfor the purpose of describing particular embodiments only, and is notintended to limit the scope of the methods and compositions describedherein, which will be limited only by the appended claims.

Unless stated otherwise, the terms used for complex moieties (i.e.,multiple chains of moieties) are to be read equivalently either fromleft to right or right to left. For example, the groupalkylenecycloalkylene refers both to an alkylene group followed by acycloalkylene group or as a cycloalkylene group followed by an alkylenegroup.

The suffix “ene” appended to a group indicates that such a group is adiradical. By way of example only, a methylene is a diradical of amethyl group, that is, it is a —CH₂— group; and an ethylene is adiradical of an ethyl group, i.e., —CH₂CH₂—.

An “alkyl” group refers to an aliphatic hydrocarbon group. The alkylmoiety includes a “saturated alkyl” group, which means that it does notcontain any alkene or alkyne moieties. The alkyl moiety also includes an“unsaturated alkyl” moiety, which means that it contains at least onealkene or alkyne moiety. An “alkene” moiety refers to a group that hasat least one carbon-carbon double bond, and an “alkyne” moiety refers toa group that has at least one carbon-carbon triple bond. The alkylmoiety, whether saturated or unsaturated, includes branched, straightchain, or cyclic moieties. Depending on the structure, an alkyl groupincludes a monoradical or a diradical (i.e., an alkylene group), and ifa “lower alkyl” having 1 to 6 carbon atoms.

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x).

The “alkyl” moiety optionally has 1 to 10 carbon atoms (whenever itappears herein, a numerical range such as “1 to 10” refers to eachinteger in the given range; e.g., “1 to 10 carbon atoms” means that thealkyl group is selected from a moiety having 1 carbon atom, 2 carbonatoms, 3 carbon atoms, etc., up to and including 10 carbon atoms,although the present definition also covers the occurrence of the term“alkyl” where no numerical range is designated). The alkyl group of thecompounds described herein may be designated as “C₁-C₄ alkyl” or similardesignations. By way of example only, “C₁-C₄ alkyl” indicates that thereare one to four carbon atoms in the alkyl chain, i.e., the alkyl chainis selected from among methyl, ethyl, propyl, iso-propyl, n-butyl,isobutyl, sec-butyl, and t-butyl. Thus C₁-C₄ alkyl includes C₁-C₂ alkyland C₁-C₃ alkyl. Alkyl groups are optionally substituted orunsubstituted. Typical alkyl groups include, but are in no way limitedto, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl,pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and the like.

The term “alkenyl” refers to a type of alkyl group in which the firsttwo atoms of the alkyl group form a double bond that is not part of anaromatic group. That is, an alkenyl group begins with the atoms—C(R)═C(R)—R, wherein R refers to the remaining portions of the alkenylgroup, which are either the same or different. The alkenyl moiety isoptionally branched, straight chain, or cyclic (in which case, it isalso known as a “cycloalkenyl” group). Depending on the structure, analkenyl group includes a monoradical or a diradical (i.e., an alkenylenegroup). Alkenyl groups are optionally substituted. Non-limiting examplesof an alkenyl group include —CH═CH₂, —C(CH₃)═CH₂, —CH═CHCH₃,—C(CH₃)═CHCH₃. Alkenylene groups include, but are not limited to,—CH═CH—, —C(CH₃)═CH—, —CH═CHCH₂—, —CH═CHCH₂CH₂— and —C(CH₃)═CHCH₂—.Alkenyl groups optionally have 2 to 10 carbons, and if a “lower alkenyl”having 2 to 6 carbon atoms.

The term “alkynyl” refers to a type of alkyl group in which the firsttwo atoms of the alkyl group form a triple bond. That is, an alkynylgroup begins with the atoms —C≡C—R, wherein R refers to the remainingportions of the alkynyl group, which is either the same or different.The “R” portion of the alkynyl moiety may be branched, straight chain,or cyclic. Depending on the structure, an alkynyl group includes amonoradical or a diradical (i.e., an alkynylene group). Alkynyl groupsare optionally substituted. Non-limiting examples of an alkynyl groupinclude, but are not limited to, —C≡CH, —C≡CCH₃, —C≡CCH₂CH₃, and—C≡CCH₂—. Alkynyl groups optionally have 2 to 10 carbons, and if a“lower alkynyl” having 2 to 6 carbon atoms.

An “alkoxy” group refers to a (alkyl)O— group, where alkyl is as definedherein.

“Hydroxyalkyl” refers to an alkyl radical, as defined herein,substituted with at least one hydroxy group. Non-limiting examples of ahydroxyalkyl include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl.

“Alkoxyalkyl” refers to an alkyl radical, as defined herein, substitutedwith an alkoxy group, as defined herein.

The term “alkylamine” refers to the —N(alkyl)_(x)H_(y) group, where xand y are selected from among x=1, y=1 and x=2, y=0. When x=2, the alkylgroups, taken together with the N atom to which they are attached,optionally form a cyclic ring system.

“Alkylaminoalkyl” refers to an alkyl radical, as defined herein,substituted with an alkylamine, as defined herein.

“Hydroxyalkylaminoalkyl” refers to an alkyl radical, as defined herein,substituted with an alkylamine, and alkylhydroxy, as defined herein.

“Alkoxyalkylaminoalkyl” refers to an alkyl radical, as defined herein,substituted with an alkylamine and substituted with an alkylalkoxy, asdefined herein.

An “amide” is a chemical moiety with the formula —C(O)NHR or —NHC(O)R,where R is selected from among alkyl, cycloalkyl, aryl, heteroaryl(bonded through a ring carbon) and heteroalicyclic (bonded through aring carbon). In some embodiments, an amide moiety forms a linkagebetween an amino acid or a peptide molecule and a compound describedherein, thereby forming a prodrug. Any amine, or carboxyl side chain onthe compounds described herein can be amidified. The procedures andspecific groups to make such amides are found in sources such as Greeneand Wuts, Protective Groups in Organic Synthesis, 3^(rd) Ed., John Wiley& Sons, New York, N.Y., 1999, which is incorporated herein by referencefor this disclosure.

The term “ester” refers to a chemical moiety with formula —COOR, where Ris selected from among alkyl, cycloalkyl, aryl, heteroaryl (bondedthrough a ring carbon) and heteroalicyclic (bonded through a ringcarbon). Any hydroxy, or carboxyl side chain on the compounds describedherein can be esterified. The procedures and specific groups to makesuch esters are found in sources such as Greene and Wuts, ProtectiveGroups in Organic Synthesis, 3^(rd) Ed., John Wiley & Sons, New York,N.Y., 1999, which is incorporated herein by reference for thisdisclosure.

As used herein, the term “ring” refers to any covalently closedstructure. Rings include, for example, carbocycles (e.g., aryls andcycloalkyls), heterocycles (e.g., heteroaryls and non-aromaticheterocycles), aromatics (e.g. aryls and heteroaryls), and non-aromatics(e.g., cycloalkyls and non-aromatic heterocycles). Rings can beoptionally substituted. Rings can be monocyclic or polycyclic.

As used herein, the term “ring system” refers to one, or more than onering.

The term “membered ring” can embrace any cyclic structure. The term“membered” is meant to denote the number of skeletal atoms thatconstitute the ring. Thus, for example, cyclohexyl, pyridine, pyran andthiopyran are 6-membered rings and cyclopentyl, pyrrole, furan, andthiophene are 5-membered rings.

The term “fused” refers to structures in which two or more rings shareone or more bonds.

The term “carbocyclic” or “carbocycle” refers to a ring wherein each ofthe atoms forming the ring is a carbon atom. Carbocycle includes aryland cycloalkyl. The term thus distinguishes carbocycle from heterocycle(“heterocyclic”) in which the ring backbone contains at least one atomwhich is different from carbon (i.e. a heteroatom). Heterocycle includesheteroaryl and heterocycloalkyl. Carbocycles and heterocycles can beoptionally substituted.

The term “aromatic” refers to a planar ring having a delocalizedπ-electron system containing 4n+2 π electrons, where n is an integer.Aromatic rings can be formed from five, six, seven, eight, nine, or morethan nine atoms. Aromatics can be optionally substituted. The term“aromatic” includes both carbocyclic aryl (e.g., phenyl) andheterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g.,pyridine). The term includes monocyclic or fused-ring polycyclic (i.e.,rings which share adjacent pairs of carbon atoms) groups.

As used herein, the term “aryl” refers to an aromatic ring wherein eachof the atoms forming the ring is a carbon atom. Aryl rings can be formedby five, six, seven, eight, nine, or more than nine carbon atoms. Arylgroups can be optionally substituted. Examples of aryl groups include,but are not limited to phenyl, naphthalenyl, phenanthrenyl, anthracenyl,fluorenyl, and indenyl. Depending on the structure, an aryl group can bea monoradical or a diradical (i.e., an arylene group).

An “aryloxy” group refers to an (aryl)O— group, where aryl is as definedherein.

The term “carbonyl” as used herein refers to a group containing a moietyselected from the group consisting of —C(O)—, —S(O)—, —S(O)2-, and—C(S)—, including, but not limited to, groups containing a least oneketone group, and/or at least one aldehyde group, and/or at least oneester group, and/or at least one carboxylic acid group, and/or at leastone thioester group. Such carbonyl groups include ketones, aldehydes,carboxylic acids, esters, and thioesters. In some embodiments, suchgroups are a part of linear, branched, or cyclic molecules.

The term “cycloalkyl” refers to a monocyclic or polycyclic radical thatcontains only carbon and hydrogen, and is optionally saturated,partially unsaturated, or fully unsaturated. Cycloalkyl groups includegroups having from 3 to 10 ring atoms. Illustrative examples ofcycloalkyl groups include the following moieties:

and the like. Depending on the structure, a cycloalkyl group is either amonoradical or a diradical (e.g., an cycloalkylene group), and if a“lower cycloalkyl” having 3 to 8 carbon atoms.

“Cycloalkylalkyl” means an alkyl radical, as defined herein, substitutedwith a cycloalkyl group. Non-limiting cycloalkylalkyl groups includecyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, and the like.

The term “heterocycle” refers to heteroaromatic and heteroalicyclicgroups containing one to four heteroatoms each selected from O, S and N,wherein each heterocyclic group has from 4 to 10 atoms in its ringsystem, and with the proviso that the ring of said group does notcontain two adjacent O or S atoms. Herein, whenever the number of carbonatoms in a heterocycle is indicated (e.g., C₁-C₆ heterocycle), at leastone other atom (the heteroatom) must be present in the ring.Designations such as “C₁-C₆ heterocycle” refer only to the number ofcarbon atoms in the ring and do not refer to the total number of atomsin the ring. It is understood that the heterocylic ring can haveadditional heteroatoms in the ring. Designations such as “4-6 memberedheterocycle” refer to the total number of atoms that are contained inthe ring (i.e., a four, five, or six membered ring, in which at leastone atom is a carbon atom, at least one atom is a heteroatom and theremaining two to four atoms are either carbon atoms or heteroatoms). Inheterocycles that have two or more heteroatoms, those two or moreheteroatoms can be the same or different from one another. Heterocyclescan be optionally substituted. Binding to a heterocycle can be at aheteroatom or via a carbon atom. Non-aromatic heterocyclic groupsinclude groups having only 4 atoms in their ring system, but aromaticheterocyclic groups must have at least 5 atoms in their ring system. Theheterocyclic groups include benzo-fused ring systems. An example of a4-membered heterocyclic group is azetidinyl (derived from azetidine). Anexample of a 5-membered heterocyclic group is thiazolyl. An example of a6-membered heterocyclic group is pyridyl, and an example of a10-membered heterocyclic group is quinolinyl. Examples of non-aromaticheterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino,thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl andquinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. The foregoing groups, as derived from the groups listedabove, are optionally C-attached or N-attached where such is possible.For instance, a group derived from pyrrole includes pyrrol-1-yl(N-attached) or pyrrol-3-yl (C-attached). Further, a group derived fromimidazole includes imidazol-1-yl or imidazol-3-yl (both N-attached) orimidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached). Theheterocyclic groups include benzo-fused ring systems and ring systemssubstituted with one or two oxo (═O) moieties such as pyrrolidin-2-one.Depending on the structure, a heterocycle group can be a monoradical ora diradical (i.e., a heterocyclene group).

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to anaromatic group that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur. An N-containing “heteroaromatic” or“heteroaryl” moiety refers to an aromatic group in which at least one ofthe skeletal atoms of the ring is a nitrogen atom. Illustrative examplesof heteroaryl groups include the following moieties:

and the like. Depending on the structure, a heteroaryl group can be amonoradical or a diradical (i.e., a heteroarylene group).

As used herein, the term “non-aromatic heterocycle”, “heterocycloalkyl”or “heteroalicyclic” refers to a non-aromatic ring wherein one or moreatoms forming the ring is a heteroatom. A “non-aromatic heterocycle” or“heterocycloalkyl” group refers to a cycloalkyl group that includes atleast one heteroatom selected from nitrogen, oxygen and sulfur. In someembodiments, the radicals are fused with an aryl or heteroaryl.Heterocycloalkyl rings can be formed by three, four, five, six, seven,eight, nine, or more than nine atoms. Heterocycloalkyl rings can beoptionally substituted. In certain embodiments, non-aromaticheterocycles contain one or more carbonyl or thiocarbonyl groups suchas, for example, oxo- and thio-containing groups. Examples ofheterocycloalkyls include, but are not limited to, lactams, lactones,cyclic imides, cyclic thioimides, cyclic carbamates,tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin,1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane,1,4-oxathiin, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine,maleimide, succinimide, barbituric acid, thiobarbituric acid,dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane,hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran,pyrroline, pyrrolidine, pyrrolidone, pyrrolidione, pyrazoline,pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane,1,3-dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline,oxazolidine, oxazolidinone, thiazoline, thiazolidine, and1,3-oxathiolane. Illustrative examples of heterocycloalkyl groups, alsoreferred to as non-aromatic heterocycles, include:

and the like. The term heteroalicyclic also includes all ring forms ofthe carbohydrates, including but not limited to the monosaccharides, thedisaccharides and the oligosaccharides. Depending on the structure, aheterocycloalkyl group can be a monoradical or a diradical (i.e., aheterocycloalkylene group).

The term “halo” or, alternatively, “halogen” or “halide” means fluoro,chloro, bromo and iodo.

The term “haloalkyl,” refers to alkyl structures in which at least onehydrogen is replaced with a halogen atom. In certain embodiments inwhich two or more hydrogen atoms are replaced with halogen atoms, thehalogen atoms are all the same as one another. In other embodiments inwhich two or more hydrogen atoms are replaced with halogen atoms, thehalogen atoms are not all the same as one another.

The term “fluoroalkyl,” as used herein, refers to alkyl group in whichat least one hydrogen is replaced with a fluorine atom. Examples offluoroalkyl groups include, but are not limited to, —CF₃, —CH₂CF₃,—CF₂CF₃, —CH₂CH₂CF₃ and the like.

As used herein, the term “heteroalkyl” refers to optionally substitutedalkyl radicals in which one or more skeletal chain atoms is aheteroatom, e.g., oxygen, nitrogen, sulfur, silicon, phosphorus orcombinations thereof. The heteroatom(s) are placed at any interiorposition of the heteroalkyl group or at the position at which theheteroalkyl group is attached to the remainder of the molecule. Examplesinclude, but are not limited to, —CH₂—O—CH₃, —CH₂—CH₂—O—CH₃,—CH₂—NH—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—N(CH₃)—CH₃, —CH₂—CH₂—NH—CH₃,—CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃,—CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃, and—CH═CH—N(CH₃)—CH₃. In addition, in some embodiments, up to twoheteroatoms are consecutive, such as, by way of example, —CH₂—NH—OCH₃and —CH₂—O—Si(CH₃)₃.

The term “heteroatom” refers to an atom other than carbon or hydrogen.Heteroatoms are typically independently selected from among oxygen,sulfur, nitrogen, silicon and phosphorus, but are not limited to theseatoms. In embodiments in which two or more heteroatoms are present, thetwo or more heteroatoms can all be the same as one another, or some orall of the two or more heteroatoms can each be different from theothers.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure.

The term “moiety” refers to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

A “thioalkoxy” or “alkylthio” group refers to a —S-alkyl group.

A “SH” group is also referred to either as a thiol group or a sulfhydrylgroup.

The term “optionally substituted” or “substituted” means that thereferenced group may be substituted with one or more additional group(s)individually and independently selected from alkyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, alkylthio,arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone,cyano, halo, acyl, nitro, haloalkyl, fluoroalkyl, amino, including mono-and di-substituted amino groups, and the protected derivatives thereof.By way of example an optional substituents may be L_(s)R_(s), whereineach L_(s) is independently selected from a bond, —O—, —C(═O)—, —S—,—S(═O)—, —S(═O)₂—, —NH—, —NHC(O)—, —C(O)NH—, S(═O)₂NH—, —NHS(═O)₂,—OC(O)NH—, —NHC(O)O—, -(substituted or unsubstituted C₁-C₆ alkyl), or-(substituted or unsubstituted C₂-C₆ alkenyl); and each R_(s) isindependently selected from H, (substituted or unsubstitutedC₁-C₄alkyl), (substituted or unsubstituted C₃-C₆cycloalkyl), heteroaryl,or heteroalkyl. The protecting groups that form the protectivederivatives of the above substituents include those found in sourcessuch as Greene and Wuts, above.

ACK Inhibitor Compounds

Described herein methods of treating solid tumors comprisingco-administering an ACK inhibitor compound (e.g., a BTK inhibitor, suchas for example an irreversible BTK inhibitor, such as for exampleibrutinib) and an HDAC inhibitor compound. In some embodiments, the HDACinhibitor is a compound of Formula (B). In some embodiments, the HDACinhibitor is3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide(i.e. PCI-24781/abexinostat).

The ACK inhibitor compounds described herein are selective for kinaseshaving an accessible cysteine that is able to form a covalent bond witha Michael acceptor moiety on the inhibitor compound. In someembodiments, the cysteine residue is accessible or becomes accessiblewhen the binding site moiety of the irreversible inhibitor binds to thekinase. That is, the binding site moiety of the irreversible inhibitorbinds to an active site of the ACK and the Michael acceptor moiety ofirreversible inhibitor gains access (in one embodiment the step ofbinding leads to a conformational change in the ACK, thus exposing thecysteine) or is otherwise exposed to the cysteine residue of the ACK; asa result a covalent bond is formed between the “S” of the cysteineresidue and the Michael acceptor of the irreversible inhibitor.Consequently, the binding site moiety of the irreversible inhibitorremains bound or otherwise blocks the active site of the ACK.

In one embodiment, the ACK is Btk, a homolog of Btk or a tyrosine kinasehaving a cysteine residue in an amino acid sequence position that ishomologous to the amino acid sequence position of cysteine 481 in Btk.In some embodiments, the ACK is HER4 Inhibitor compounds describedherein include a Michael acceptor moiety, a binding site moiety and alinker that links the binding site moiety and the Michael acceptormoiety (and in some embodiments, the structure of the linker provides aconformation, or otherwise directs the Michael acceptor moiety, so as toimprove the selectivity of the irreversible inhibitor for a particularACK).

In some embodiments, the ACK inhibitor is a compound of Formula (A):

wherein

-   -   A is independently selected from N or CR₅;    -   R₁ is H, L₂-(substituted or unsubstituted alkyl),        L₂-(substituted or unsubstituted cycloalkyl), L₂-(substituted or        unsubstituted alkenyl), L₂-(substituted or unsubstituted        cycloalkenyl), L₂-(substituted or unsubstituted heterocycle),        L₂-(substituted or unsubstituted heteroaryl), or L₂-(substituted        or unsubstituted aryl), where L₂ is a bond, O, S, —S(═O),        —S(═O)₂, C(═O), -(substituted or unsubstituted C₁-C₆ alkyl), or        -(substituted or unsubstituted C₂-C₆ alkenyl);    -   R₂ and R₃ are independently selected from H, lower alkyl and        substituted lower alkyl;    -   R₄ is L₃-X-L₄-G, wherein,        -   L₃ is optional, and when present is a bond, optionally            substituted or unsubstituted alkyl, optionally substituted            or unsubstituted cycloalkyl, optionally substituted or            unsubstituted alkenyl, optionally substituted or            unsubstituted alkynyl;        -   X is optional, and when present is a bond, O, —C(═O), S,            —S(═O), —S(═O)₂, —NH, —NR₉, —NHC(O), —C(O)NH, —NR₉C(O),            —C(O)NR₉, —S(═O)₂NH, —NHS(═O)₂, —S(═O)₂NR₉—, —NR₉S(═O)₂,            —OC(O)NH—, —NHC(O)O—, —OC(O)NR₉—, —NR₉C(O)O—, —CH═NO—,            —ON═CH—, —NR₁₀C(O)NR₁₀—, heteroaryl, aryl,            —NR₁₀C(═NR₁)NR₁₀—, —NR₁₀C(═NR₁₁)—, —C(═NR₁₁)NR₁₀—,            —OC(═NR₁₁)—, or —C(═NR₁₁)O—;        -   L₄ is optional, and when present is a bond, substituted or            unsubstituted alkyl, substituted or unsubstituted            cycloalkyl, substituted or unsubstituted alkenyl,            substituted or unsubstituted alkynyl, substituted or            unsubstituted aryl, substituted or unsubstituted heteroaryl,            substituted or unsubstituted heterocycle;        -   or L₃, X and L₄ taken together form a nitrogen containing            heterocyclic ring;        -   G is

wherein, R₆, R₇ and R₈ are independently selected from among H, loweralkyl or substituted lower alkyl, lower heteroalkyl or substituted lowerheteroalkyl, substituted or unsubstituted lower cycloalkyl, andsubstituted or unsubstituted lower heterocycloalkyl;

-   -   R₅ is H, halogen, -L₆-(substituted or unsubstituted C₁-C₃        alkyl), -L₆-(substituted or unsubstituted C₂-C₄ alkenyl),        -L₆-(substituted or unsubstituted heteroaryl), or        -L₆-(substituted or unsubstituted aryl), wherein L₆ is a bond,        O, S, —S(═O), S(═O)₂, NH, C(O), —NHC(O)O, —OC(O)NH, —NHC(O), or        —C(O)NH;    -   each R₉ is independently selected from among H, substituted or        unsubstituted lower alkyl, and substituted or unsubstituted        lower cycloalkyl;    -   each R₁₀ is independently H, substituted or unsubstituted lower        alkyl, or substituted or unsubstituted lower cycloalkyl; or    -   two R₁₀ groups can together form a 5-, 6-, 7-, or 8-membered        heterocyclic ring; or    -   R₉ and R₁₀ can together form a 5-, 6-, 7-, or 8-membered        heterocyclic ring; or    -   each R₁₁ is independently selected from H, —S(═O)₂R₈,        —S(═O)₂NH₂, —C(O)R₈, —CN, —NO₂, heteroaryl, or heteroalkyl; and        pharmaceutically active metabolites, pharmaceutically acceptable        solvates, pharmaceutically acceptable salts, or pharmaceutically        acceptable prodrugs thereof.

In some embodiments, the ACK inhibitor isR)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one(i.e. PCI-32765/ibrutinib)

In some embodiments, the ACK inhibitor is AVL-263 (AvilaTherapeutics/Celgene Corporation), AVL-292 (Avila Therapeutics/CelgeneCorporation), AVL-291 (Avila Therapeutics/Celgene Corporation),BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb),CGI-1746 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech),HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21,HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co.,Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (PekingUniversity), RN486 (Hoffmann-La Roche), or HM71224 (Hanmi PharmaceuticalCompany Limited).

In some embodiments, the ACK inhibitor is4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)benzamide(CGI-1746);7-benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo[4,5-g]quinoxalin-6(5H)-one(CTA-056);(R)—N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide(GDC-0834);6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one(RN-486);N-[5-[5-(4-acetylpiperazine-1-carbonyl)-4-methoxy-2-methylphenyl]sulfanyl-1,3-thiazol-2-yl]-4-[(3,3-dimethylbutan-2-ylamino)methyl]benzamide(BMS-509744, HY-11092); orN-(5-((5-(4-Acetylpiperazine-1-carbonyl)-4-methoxy-2-methylphenyl)thio)thiazol-2-yl)-4-(((3-methylbutan-2-yl)amino)methyl)benzamide(HY11066).

In some embodiments, the ACK inhibitor is:

HDAC Inhibitor Compounds

Described herein methods of treating solid tumors comprisingco-administering an ACK inhibitor compound (e.g., a BTK inhibitor, suchas for example an irreversible BTK inhibitor, such as for exampleibrutinib) and an HDAC inhibitor compound. In some embodiments, the ACKinhibitor compound (e.g., a BTK inhibitor, such as for example anirreversible BTK inhibitor, such as for example ibrutinib) is a compoundof Formula (A). In some embodiments, the ACK inhibitor compound is(R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one(i.e. PCI-32765/ibrutinib).

In some embodiments, the ACK inhibitor is AVL-263 (AvilaTherapeutics/Celgene Corporation), AVL-292 (Avila Therapeutics/CelgeneCorporation), AVL-291 (Avila Therapeutics/Celgene Corporation),BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb),CGI-1746 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech),HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21,HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co.,Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (PekingUniversity), RN486 (Hoffmann-La Roche), or HM71224 (Hanmi PharmaceuticalCompany Limited).

In some embodiments, the HDAC inhibitor has the structure of Formula(B):

wherein:R¹ is hydrogen or alkyl;X is —O—, —NR²—, or —S(O)_(n) where n is 0-2 and R² is hydrogen oralkyl;Y is alkylene optionally substituted with cycloalkyl, optionallysubstituted phenyl, alkylthio, alkylsulfinyl, alkysulfonyl, optionallysubstituted phenylalkylthio, optionally substituted phenylalkylsulfonyl,hydroxy, or optionally substituted phenoxy;Ar¹ is phenylene or heteroarylene wherein said Ar¹ is optionallysubstituted with one or two groups independently selected from alkyl,halo, hydroxy, alkoxy, haloalkoxy, or haloalkyl;R³ is hydrogen, alkyl, hydroxyalkyl, or optionally substituted phenyl;andAr² is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl,heteroaralkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, orheterocycloalkylalkyl;and individual stereoisomers, individual geometric isomers, or mixturesthereof; or a pharmaceutically acceptable salt thereof.

In some embodiments, the histone deacetylase inhibitor is3-((dimethylamino)methyl)-N-(2-(4-(hydroxycarbamoyl)phenoxy)ethyl)benzofuran-2-carboxamide(i.e. PCI-24781/abexinostat).

Pharmaceutical Compositions/Formulations

Disclosed herein, in certain embodiments, are compositions comprising atherapeutically effective amount of an ACK inhibitor compound and/or atherapeutically effective amount of an HDAC inhibitor compound, and apharmaceutically acceptable excipient. Further disclosed herein, incertain embodiments, are compositions comprising a therapeuticallyeffective amount of an ACK inhibitor compound, a therapeuticallyeffective amount of an HDAC inhibitor compound, and a pharmaceuticallyacceptable excipient. In some embodiments, the ACK inhibitor compound(e.g., a BTK inhibitor, such as for example an irreversible BTKinhibitor, such as for example ibrutinib) is a compound of Formula (A).In some embodiments, the ACK inhibitor compound is(R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one(i.e. PCI-32765/ibrutinib). In some embodiments, the ACK inhibitor isAVL-263 (Avila Therapeutics/Celgene Corporation), AVL-292 (AvilaTherapeutics/Celgene Corporation), AVL-291 (Avila Therapeutics/CelgeneCorporation), BMS-488516 (Bristol-Myers Squibb), BMS-509744(Bristol-Myers Squibb), CGI-1746 (CGI Pharma/Gilead Sciences), CTA-056,GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22,HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (OnoPharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.),PLS-123 (Peking University), RN486 (Hoffmann-La Roche), or HM71224(Hanmi Pharmaceutical Company Limited). In some embodiments, the HDACinhibitor is a compound of Formula (B). In some embodiments, the HDACinhibitor is3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide(i.e. PCI-24781/abexinostat).

Pharmaceutical compositions of ACK inhibitor compound (e.g., a BTKinhibitor, such as for example an irreversible BTK inhibitor, such asfor example ibrutinib) and/or HDAC inhibitor compound are formulated ina conventional manner using one or more physiologically acceptablecarriers including excipients and auxiliaries which facilitateprocessing of the active compounds into preparations which can be usedpharmaceutically. Proper formulation is dependent upon the route ofadministration chosen. A summary of pharmaceutical compositionsdescribed herein is found, for example, in Remington: The Science andPractice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack PublishingCompany, 1995); Hoover, John E., Remington's Pharmaceutical Sciences,Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. and Lachman, L.,Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980;and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed.(Lippincott Williams & Wilkins 1999).

A pharmaceutical composition, as used herein, refers to a mixture of anACK inhibitor compound (e.g., a BTK inhibitor, such as for example anirreversible BTK inhibitor, such as for example ibrutinib) and/or HDACinhibitor compound with other chemical components, such as carriers,stabilizers, diluents, dispersing agents, suspending agents, thickeningagents, and/or excipients.

Pharmaceutical compositions are optionally manufactured in aconventional manner, such as, by way of example only, by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or compression processes.

The pharmaceutical formulations described herein are administered by anysuitable administration route, including but not limited to, oral,parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal,buccal, topical, rectal, or transdermal administration routes.

The pharmaceutical compositions described herein are formulated into anysuitable dosage form, including but not limited to, aqueous oraldispersions, liquids, gels, syrups, elixirs, slurries, suspensions andthe like, for oral ingestion by an individual to be treated, solid oraldosage forms, aerosols, controlled release formulations, fast meltformulations, effervescent formulations, lyophilized formulations,tablets, powders, pills, dragees, capsules, delayed releaseformulations, extended release formulations, pulsatile releaseformulations, multiparticulate formulations, and mixed immediate releaseand controlled release formulations. In some embodiments, thecompositions are formulated into capsules. In some embodiments, thecompositions are formulated into solutions (for example, for IVadministration).

The pharmaceutical solid dosage forms described herein optionallyinclude a compound described herein and one or more pharmaceuticallyacceptable additives such as a compatible carrier, binder, fillingagent, suspending agent, flavoring agent, sweetening agent,disintegrating agent, dispersing agent, surfactant, lubricant, colorant,diluent, solubilizer, moistening agent, plasticizer, stabilizer,penetration enhancer, wetting agent, anti-foaming agent, antioxidant,preservative, or one or more combination thereof.

In still other aspects, using standard coating procedures, such as thosedescribed in Remington's Pharmaceutical Sciences, 20th Edition (2000), afilm coating is provided around the compositions. In some embodiments,the compositions are formulated into particles (for example foradministration by capsule) and some or all of the particles are coated.In some embodiments, the compositions are formulated into particles (forexample for administration by capsule) and some or all of the particlesare microencapsulated. In some embodiments, the compositions areformulated into particles (for example for administration by capsule)and some or all of the particles are not microencapsulated and areuncoated.

In some embodiments, the pharmaceutical compositions are formulated suchthat the amount of the ACK inhibitor (e.g., a BTK inhibitor, such as forexample an irreversible BTK inhibitor, such as for example ibrutinib) ineach unit dosage form is about 140 mg per.

Kits/Articles of Manufacture

Described herein methods of treating solid tumors comprisingco-administering an ACK inhibitor compound (e.g., a BTK inhibitor, suchas for example an irreversible BTK inhibitor, such as for exampleibrutinib) and an HDAC inhibitor compound. In some embodiments, the ACKinhibitor compound (e.g., a BTK inhibitor, such as for example anirreversible BTK inhibitor, such as for example ibrutinib) is a compoundof Formula (A). In some embodiments, the ACK inhibitor compound is(R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one(i.e. PCI-32765/ibrutinib). In some embodiments, the ACK inhibitor isAVL-263 (Avila Therapeutics/Celgene Corporation), AVL-292 (AvilaTherapeutics/Celgene Corporation), AVL-291 (Avila Therapeutics/CelgeneCorporation), BMS-488516 (Bristol-Myers Squibb), BMS-509744(Bristol-Myers Squibb), CGI-1746 (CGI Pharma/Gilead Sciences), CTA-056,GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22,HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (OnoPharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.),PLS-123 (Peking University), RN486 (Hoffmann-La Roche), or HM71224(Hanmi Pharmaceutical Company Limited). In some embodiments, the HDACinhibitor is a compound of Formula (B). In some embodiments, the HDACinhibitor is3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide(i.e. PCI-24781/abexinostat).

For use in therapeutic applications described herein, kits and articlesof manufacture are also described herein. In some embodiments, such kitsinclude a carrier, package, or container that is compartmentalized toreceive one or more containers such as vials, tubes, and the like, eachof the container(s) including one of the separate elements to be used ina method described herein. Suitable containers include, for example,bottles, vials, syringes, and test tubes. The containers can be formedfrom a variety of materials such as glass or plastic.

The articles of manufacture provided herein contain packaging materials.Examples of pharmaceutical packaging materials include, but are notlimited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials,containers, syringes, bottles, and any packaging material suitable for aselected formulation and intended mode of administration and treatment.A wide array of formulations of the compounds and compositions providedherein are contemplated as are a variety of treatments for any disorderthat benefit by inhibition of Btk, or in which Btk is a mediator orcontributor to the symptoms or cause.

For example, a container may include one or both of the irreversible BTKinhibitor and HDAC inhibitor compounds. The container(s) optionally havea sterile access port (for example the container is an intravenoussolution bag or a vial having a stopper pierceable by a hypodermicinjection needle). Such kits optionally comprising a compound with anidentifying description or label or instructions relating to its use inthe methods described herein.

A kit will typically include one or more additional containers, eachwith one or more of various materials (such as reagents, optionally inconcentrated form, and/or devices) desirable from a commercial and userstandpoint for use of a compound described herein. Non-limiting examplesof such materials include, but not limited to, buffers, diluents,filters, needles, syringes; carrier, package, container, vial and/ortube labels listing contents and/or instructions for use, and packageinserts with instructions for use. A set of instructions will alsotypically be included.

In some embodiments, a label is on or associated with the container. Alabel can be on a container when letters, numbers or other charactersforming the label are attached, molded or etched into the containeritself; a label can be associated with a container when it is presentwithin a receptacle or carrier that also holds the container, e.g., as apackage insert. A label can be used to indicate that the contents are tobe used for a specific therapeutic application. The label can alsoindicate directions for use of the contents, such as in the methodsdescribed herein.

In certain embodiments, a pharmaceutical composition comprising one orboth the ACK inhibitor compound (e.g., a BTK inhibitor, such as forexample an irreversible BTK inhibitor, such as for example ibrutinib)and the HDAC inhibitor compounds is presented in a pack or dispenserdevice which can contain one or more unit dosage forms. The pack can forexample contain metal or plastic foil, such as a blister pack. The packor dispenser device can be accompanied by instructions foradministration. The pack or dispenser can also be accompanied with anotice associated with the container in form prescribed by agovernmental agency regulating the manufacture, use, or sale ofpharmaceuticals, which notice is reflective of approval by the agency ofthe form of the drug for human or veterinary administration. Suchnotice, for example, can be the labeling approved by the U.S. Food andDrug Administration for prescription drugs, or the approved productinsert. Compositions containing a compound provided herein formulated ina compatible pharmaceutical carrier can also be prepared, placed in anappropriate container, and labeled for treatment of an indicatedcondition.

EXAMPLES

The following specific and non-limiting examples are to be construed asmerely illustrative, and do not limit the present disclosure in any waywhatsoever.

Example 1

The aim of the experiment is to evaluate the effect of two drugs ontumor development in a mouse model of non-small cell lung cancer.

The two drugs tested were Abexinostat (PCI-24781), and Ibrutinib(PCI-32765).

Grg1 transgenic mice were used to evaluate the drugs. Grg1 transgenicmice overexpress the Groucho-related gene 1 (Grg1). The mice developlung tumors that resemble human non-small cell lung cancer. Tumorsinitiate at 1 month of age and progress to invasive adenocarcinoma by 8months of age. The drugs were administered to 2 month-old mice or to 5month-old mice, and mice were treated for 4 weeks. The former group isreferred to as the 3 month samples and the latter as the 6 monthsamples.

Summary

Drug treatment of 2 to 3 month old mice reduced tumor number compared tothe control group. The combination of abexinostat and ibrutinib reducedtumor number by 75%.

With the combination of abexinostat and ibrutinib treatment for 5 to 6months, there were no large tumors.

Methods

a. Mice

Mice were housed and treated following the applicable Standard OperatingProcedures and according to the Canadian Animal Care Committeestandards.

Mice were bred to generate double transgenic (Grg1/Cre recombinase) miceon a CD1 background. Four groups of female double transgenic mice wereestablished:

Group 1—Control (no treatment, injection of PBS, or water with carrierand no drug)

Group 2—Abexinostat—treated

Group 3—Ibrutinib—treated

Group 4—Abexinostat+Ibrutinib—treated

At least 8 mice in each group were treated at 2 months old and 8 mice ineach group were treated at 5 months old. Treatments lasted 4 weeks, andmice were sacrificed at 3 months and 6 months. Therefore samples arereferred to as 3 month samples or 6 month samples.

b. Drug Preparation and Dosage

Abexinostat was administered by intraperitoneal (i.p.) injection, twiceper day for five days each week. Mice were weighed and injected with 6μl per gram body weight of a 1 mg/ml solution. The dosage was 12 mg/kgBID.

Ibrutinib was administered by supplying it in the drinking water, for adosage of ˜22 mg/kg/day.

Mice were treated for 4 weeks. After treatment, mice were euthanized andlung tissue was examined.

Drugs were prepared and administered as follows:

Abexinostat

Formulation: Add DMSO to powder stock in vial to make a 200 mg/mlsolution. Aliquot out into 100 μl. Every two weeks, as required, thaw a100 μl aliquot and add 900 μl sterile water. Aliquot into 20 μl aliquotsof 20 mg/ml. Store this stock at 4 C.

Dosage

20 μl of 20 mg/ml stock in the fridge; inject at 1 mg/ml concentrationin sterile water. On the day of injection, add 380 μl sterile water orPBS and pipet well to mix thoroughly. Inject 6 μl per g body weightTWICE DAILY.

Ibrutinib

Formulation: 100 ml of the 10× concentrate of Ibrutinib. Dilute 1 partof concentrate with 9 parts water. Both the 10× and 1× dilutions can bestored at room temperature. PCI-32765 is >99% stable in this formulationafter 6 weeks at room temperature (22° C.).

Dosage

Administered by drinking water; Average consumption is ˜4 mL/day/mouse,corresponding to a final dose of ˜22 mg/kg/day. Thus 4 ml×4 mice=16ml/day×7 days=140 ml per week

c. Quantitation

For quantitation of tumors, the total visible tumors on the lung surfacewere counted using a dissecting microscope. In addition, the left lunglobe was fixed in 4% PFA, paraffin-embedded and 5 μm sections were takenfor 100 μm at two levels. The first level began 30 μm below the lungsurface and the second level began 130 μm below the lung surface.Alternate slides were H&E stained, and tumors were detected and countedusing a dissecting microscope. Tumor diameter was measured using aninverted microscope and reticule.

The right lung lobes were snap-frozen and stored for DNA or proteinanalysis.

d. Blood Samples

For 6 month-old mice, blood samples were collected in EDTA tubes, andperipheral blood mononuclear cells (PBMC) and plasma were prepared,frozen and stored as follows:

1. A minimum of 500 μL of blood is drawn into the EDTA tube

2. Transfer the blood into 1.5 mL eppendort tubes and centrifuge at350×g for 5 minutes to separate the plasma and the cells.

3. Save the supernatant/plasma.

4. Add 1 ml of 1×RBC Lysis Buffer (Sigma #R7757) to the pellet

5. Gently vortex each tube immediately after adding the lysing solution.

6. Incubate at room temperature, protected from light, for 5 minutes.

7. Centrifuge 350×g for 2 minutes.

8. Aspirate supernatant without disturbing pellet.

9. Wash the pellet once with 1 mL of PBS to the sample and centrifuge350×g for 2 minutes

10. Aspirate supernatant without disturbing the pellet.

11. Freeze the PBMC pellet at ˜80 C

Results

a. Three Month Old

The total number of surface tumors visible at 3 months, after 4 weeks oftreatment, is shown in a table and corresponding bar graph in FIG. 2.Each number in the table represents the number of tumors in one mouse.The average number of tumors per mouse for each treatment is shown inthe bottom row of the table and right-most bar for each group. For thecontrol group, the average number of tumors was 5.9 (n=10). For theAbexinostat-treated mice, the average tumor number was 3.0 (n=10), forIbrutinib it was 2.6 (n=8), and for treatment with both drugs 1.4(n=11).

Tumors in the 3 month samples were further analyzed for four mice ineach treatment group by sectioning the left lung lobe, and H&E stainingalternate slides. The tumor histology is presented in FIG. 3 and allimages are available on disk.

The tumors are carcinoma that are less than 400 The tumor histologyappears similar in treated and control mice.

b. Six Month Old

The total number of surface tumors visible at 6 months, after 4 weeks oftreatment, is shown in a table and corresponding bar graph in FIG. 4.Each number in the table represents the number of tumors in one mouse.The average number of tumors per mouse for each treatment is shown inthe bottom row and the right-most bar for each group. For the controlgroup, the average number of tumors was 7.8 (n=8). For theAbexinostat-treated mice, the average tumor number was 4.6 (n=8), forIbrutinib it was 7.6 (n=5), and for treatment with both drugs 8.4 (n=5).

The number of visible surface tumors in the 6 month-old mice was quitevariable and did not show a trend between treatment groups.

The tumors were further analyzed for two to four mice in each group bysectioning the left lung lobe, and H&E staining alternate slides. Tomeasure and compare the tumor load in the mice in the 6 month samples,the tumor diameter in the tissue sections was measured. The number oftumors in the sections and the size of each tumor is recorded in thetable and corresponding bar graph in FIG. 5. Each column in the tableand group of bars in the graph shows the tumor sizes for one mouse.

The treated mice had fewer large tumors than the control mice. Thenumber of tumors over 1 mm in diameter for each mouse is shown in FIG.6. Control mice had an average of 1.5 large tumors per mouse,Abexinostat- and Ibrutinib-treated mice had an average of 0.5 largetumors per mouse and Abexinostat+Ibrutinib-treated mice had 0 largetumors per mouse.

Images of the whole left lung lobe from control and treated mice areshown in FIG. 7 and the tissue sections showing the tumor histology areshown in FIG. 8.

Conclusion

The data analysis reveals that both Abexinostat and Ibrutinib greatlyreduce tumor number in mice treated from 2 to 3 months and the drugsappear to act synergistically. The reduction was 50-60% for each drugalone and 75% when the drugs were used together. Although the drugsreduce tumor number, the tumors appear morphologically similar betweentreated and control samples at 3 months.

At 6 months, the tumor number is variable, but in treated mice thenumber of large tumors (over 1 mm) is much lower. The drugs also appearto act synergistically at this stage to reduce the number of largetumors. The tumors for control and treated mice have lymphocyteinfiltration. However tumors in mice receiving Abexinostat have a highnumber of apoptotic cells. Tumors in mice receiving Ibrutinib lack thehigh number of apoptotic macrophages seen in the control andAbexinostat-treated mice, and have less tumor necrosis than the controlsamples.

Example 2 Clinical Trial for Pancreatic Cancer

Study Type: Interventional

Study Design: Allocation: Non-Randomized

Endpoint Classification: Safety/Efficacy Study

Intervention Model: Single Group Assignment

Masking: Open Label

Primary Purpose: Treatment

Primary Outcome Measures: To assess the response rate associated withibrutinib and abexinostat in patients with advanced pancreatic cancer

Secondary Outcome Measures: To assess the side effects of ibrutinib andabexinostat in patients with advanced pancreatic cancer

Detailed Description

Patients will be treated three times daily ibrutinib (140 mg/dose) andonce daily with abexinostat for 4 consecutive days, followed by 3 daysoff of abexinostat (a cycle is 7 days). At day 1 of each cycle aphysical exam and blood work will be performed. Reassessment of tumorsize will be conducted at 6 weeks, 12 weeks and then every 9 weeksthereafter. Patients will remain on treatment until one of the followingoccur: disease progression, illness that prevents further treatment orunacceptable adverse events.

Eligibility

Ages Eligible for Study: 18 Years and older

Genders Eligible for Study: Both

Accepts Healthy Volunteers: No

Inclusion Criteria:

Metastatic pancreatic carcinoma (excluding pancreatic endocrine tumors)

Only patients with measurable disease

ECOG performance status<or equal to 1

Life expectancy>12 weeks

Signed informed consent

Failed or intolerance to first-line therapy for metastatic disease witha gemcitabine-containing regimen. Patients may have received adjuvanttherapy in addition to one prior regimen for metastatic disease.

>4 weeks must have elapsed from the completion of previous chemotherapyand patients must have recovered from any related toxicities

>4 weeks must have elapsed from the participation in any investigationaldrug study

Laboratory values: ANC>1500/mm3; Hemoglobin>9.0 gm/dl;Platelets>100,000/mm3; SGOT<2.5× upper limit of normal; or <5× upperlimit of normal if evidence of liver metastases; Alkalinephosphatase<2.5× upper limit of normal; or <5× upper limit of normal ifevidence of liver metastases; Total bilirubin<1.5× upper limit ofnormal; Creatinine clearance>50 cc/min (by Cockroft-Gault or asdetermined from a 24-hour urine collection).

Exclusion Criteria:

More than one prior chemotherapy treatment regimen for metastaticdisease

Clinically apparent central nervous system (CNS) metastases orcarcinomatous meningitis

Clinically significant cardiac disease (e.g. congestive heart failure,symptomatic coronary artery disease and cardiac arrhythmias not wellcontrolled with medication or heart attack within the last 12 months).

Major surgery within 4 weeks of the start of study treatment, withoutcomplete recovery.

Evidence of CNS metastases (unless CNS metastases have been stablefor >3 months) or history of uncontrolled seizures, central nervoussystem disorders

Uncontrolled serious medical or psychiatric illness

Women must not be pregnant or lactating

Concurrent radiation therapy

Other active malignancy

Inability to swallow capsules

Patients lacking physical integrity of the upper gastrointestinal tractor who have malabsorption syndrome

Example 3 Colon Cancer

Study Type: Interventional

Study Design: Allocation: Randomized

Endpoint Classification: Efficacy Study

Intervention Model: Parallel Assignment

Masking: Double Blind (Subject, Investigator)

Primary Outcome Measures: Disease-free Survival following therapy withibrutinib and abexinostat

Secondary Outcome Measures: Survival as Assessed by Death From Any Cause

Detailed Description

Patients will be treated three times daily ibrutinib (140 mg/dose) andonce daily with abexinostat for 4 consecutive days, followed by 3 daysoff of abexinostat (a cycle is 7 days). At day 1 of each cycle aphysical exam and blood work will be performed. Reassessment of tumorsize will be conducted at 6 weeks, 12 weeks and then every 9 weeksthereafter. Patients will remain on treatment until one of the followingoccur: disease progression, illness that prevents further treatment orunacceptable adverse events.

Eligibility

Ages Eligible for Study: 18 Years and older

Genders Eligible for Study: Both

Accepts Healthy Volunteers: No

Inclusion Criteria:

Patients must consent to be in the study and must have signed and datedan IRB approved consent form conforming to federal and institutionalguidelines

Randomization must occur during the three-week interval beginning onpostoperative day 29 and ending on postoperative day 50

The distal extent of the tumor must be >=12 cm from the anal verge onendoscopy; if the patient is not a candidate for endoscopy, then thedistal extent of the tumor must be >=12 cm from the anal verge asdetermined by surgical examination

The patient must have had an en bloc complete gross resection of tumor(curative resection) by open laparotomy or laparoscopically-assistedcolectomy; patients who have had a two-stage surgical procedure, tofirst provide a decompressive colostomy and then in a later procedure tohave the definitive surgical resection, are eligible

Patients must have histologically confirmed adenocarcinoma of the colonthat meets one of the following criteria: Stage II carcinoma (T3,4 N0M0); the tumor invades through the muscularis propria into the subserosaor into non-peritonealized pericolic or perirectal tissues (T3); ordirectly invades other organs or structures, and/or perforates visceralperitoneum (T4); Stage III carcinoma (any T N1,2 M0); the tumor hasinvaded to any depth, with involvement of regional lymph nodes

Patients with T4 tumors that have involved an adjacent structure (e.g.,bladder, small intestine, ovary, etc.) by direct extension from theprimary tumor are eligible if all of the following conditions are met:All or a portion of the adjacent structure was removed en bloc with theprimary tumor; In the opinion of the surgeon, all grossly visible tumorwas completely resected (“curative resection”); Histologic evaluation bythe pathologist confirms the margins of the resected specimen are notinvolved by malignant cells; and Local radiation therapy will not beutilized

Patients with more than one synchronous primary colon tumor areeligible; (staging classification will be based on the more advancedprimary tumor)

Patients must have an ECOG performance status of 0 or 1

At the time of randomization, postoperative absolute granulocyte count(AGC) must be >=1500/mm^3 (or <1500/mm^3, if in the opinion of theinvestigator, this represents an ethnic or racial variation of normal)

At the time of randomization, the postoperative platelet count must be>=100,000/mm^3

Bilirubin must be =<ULN for the lab unless the patient has a chronicgrade 1 bilirubin elevation due to Gilbert's disease or similar syndromedue to slow conjugation of bilirubin

Alkaline phosphatase must be <2.5×ULN for the lab

AST must be <1.5×ULN for the lab. If AST is >ULN, serologic testing forhepatitis B and C must be performed and results must be negative

Serum creatinine=<1.5×ULN for the lab

Urine protein/creatinine (UPC) ratio of <1.0; patients with a UPCratio>=1.0 must undergo a 24-hour urine collection, which must be anadequate collection and must demonstrate <1 gm of protein in the 24-hoururine collection in order to participate in the study

Patients with prior malignancies, including colorectal cancers, areeligible if they have been disease-free for >=5 years and are deemed bytheir physician to be at low risk for recurrence; patients with squamousor basal cell carcinoma of the skin, melanoma in situ, carcinoma in situof the cervix, or carcinoma in situ of the colon or rectum that havebeen effectively treated are eligible, even if these conditions werediagnosed within 5 years prior to randomization

Exclusion Criteria:

Patients<18 years old

Colon tumor other than adenocarcinoma

Rectal tumors, i.e. a tumor located <12 cm from the anal verge onendoscopy, or by surgical exam if the patient is not a candidate forendoscopy

Isolated, distant, or non-contiguous intra-abdominal metastases, even ifresected

Any systemic or radiation therapy initiated for this malignancy

Any significant bleeding that is not related to the primary colon tumorwithin 6 months before study entry

Serious or non-healing wound, skin ulcers, or bone fracture

Gastroduodenal ulcer(s) determined by endoscopy to be active

Invasive procedures defined as follows: Major surgical procedure, openbiopsy, or significant traumatic injury within 28 days prior torandomization; Anticipation of need for major surgical procedures duringthe course of the study; Core biopsy or other minor procedure, excludingplacement of a vascular access device, within 7 days prior torandomization

Uncontrolled blood pressure defined as >150/90 mmHg

History of TIA or CVA

History of arterial thrombotic event within 12 months before study entry

Symptomatic Peripheral Vascular Disease

PT/INR>1.5, unless the patient is on therapeutic doses of warfarin. Ifso, the following criteria must be met for enrollment: The subject musthave an in-range INR (usually between 2 and 3) on a stable dose ofwarfarin; The subject must not have active bleeding or a pathologicalcondition that is associated with a high-risk of bleeding

Concomitant halogenated antiviral agents

Clinically significant peripheral neuropathy at the time ofrandomization (defined in the NCI Common Terminology Criteria forAdverse Events Version 3.0 [CTCAE v3.0] as grade 2 or greaterneurosensory or neuromotor toxicity)

Non-malignant systemic disease (cardiovascular, renal, hepatic, etc.)that would preclude any of the study therapy drugs; specificallyexcluded are the following cardiac conditions: New York HeartAssociation Class III or IV cardiac disease; History of myocardialinfarction within 12 months before study entry; Unstable angina within12 months before study entry; and Symptomatic arrhythmia

History of chronic or persistent viral hepatitis or other chronic liverdisease

Psychiatric or addictive disorders or other conditions that, in theopinion of the investigator, would preclude the patient from meeting thestudy requirements

Example 4 Breast and Ovarian Cancer

Study Type: Interventional

Study Design: Allocation: Non-Randomized

Endpoint Classification: Safety Study

Intervention Model: Single Group Assignment

Masking: Open Label

Primary Purpose: Treatment

Primary Outcome Measures: Determine the safety and toxicity of thecombination of ibrutinib and abexinostat in BRCA 1/2-associatedrecurrent breast and ovarian cancer patients

Secondary Outcome Measures: Assess clinical activity of the combination;

Detailed Description

Patients will be treated three times daily ibrutinib (140 mg/dose) andonce daily with abexinostat for 4 consecutive days, followed by 3 daysoff of abexinostat (a cycle is 7 days). At day 1 of each cycle aphysical exam and blood work will be performed. Reassessment of tumorsize will be conducted at 6 weeks, 12 weeks and then every 9 weeksthereafter. Patients will remain on treatment until one of the followingoccur: disease progression, illness that prevents further treatment orunacceptable adverse events.

Eligibility

Ages Eligible for Study: 18 Years and older

Genders Eligible for Study: Both

Accepts Healthy Volunteers: No

Inclusion Criteria

Patients must have breast and/or epithelial ovarian cancer, primaryperitoneal cancer, and/or fallopian tube cancer histologically orcytologically confirmed at the NCI that is metastatic or unresectableand for which standard curative measures do not exist or are no longereffective.

All patients in cohort 1 must have measurable and/or evaluable disease.

Patients in the expansion cohort 2 must have safely biopsible disease asdetermine by an interventional radiologist and must agree to the firstmandatory biopsy (the other two biopsies optional).

Breast cancer patients with locally advanced, unresectable disease musthave been previously treated with standard therapy.

There is no limit on number of prior therapy.

ECOG performance status less than or equal to 2 (Karnofsky greater thanor equal to 60%).

Life expectancy greater than 3 months.

Patients must have normal organ and marrow function defined as follows:hemoglobin greater than or equal to 10 g/dL; leukocytes greater than orequal to 3,000/mcL; absolute neutrophil count greater than or equal to1,500/mcL; platelets greater than or equal to 100,000/mcL; totalbilirubin less than or equal to upper limit of normal (ULN) in theabsence of Gilbert's syndrome; AST(SGOT)/ALT(SGPT) less than or equal to2.5×ULN; creatinine clearance greater than or equal to 60 mL/min by24-hour urine; corrected or Ionized Calcium less than or equal to ULN;potassium within normal limits

A documented deleterious BRCA 1/2 germline mutation or BRCAPRO score ofgreater than or equal to 30% for patients enrolling in Group A.

For patients enrolling in the sporadic serous epithelial ovarian cancergroup, Group B, a negative family history (BRCAPRO score less than orequal to 20% or negative BRCA1/2 mutation test).

For patients enrolling in the triple negative breast cancer(ER-/PR-/Her2-) group, Group B, a negative family history and/or BRCAPROscore less than or equal to 10% or negative BRCA1/2 mutation test).

Exclusion Criteria

Patients who have had chemotherapy, biological therapy, hormonal therapy(with the exception of raloxifene or others approved for bone health) orradiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C)prior to entering the study.

Patients may not be receiving any other investigational agents or hadthem in the previous 28 days.

Patients with known brain metastases diagnosed within 1 year should beexcluded from this clinical trail because of their poor prognosis andbecause they often develop progressive neurological dysfunction thatwould confound the evaluation of neurologic and other adverse events.

Clinically significant bleeding.

Inability to swallow capsules.

Uncontrolled intercurrent illness including, but not limited to, ongoingor active infection, symptomatic congestive heart failure, unstableangina pectoris, cardiac arrhythmia, or psychiatric illness/socialsituations that would limit compliance with study requirements.

Pregnant and breast-feeding women.

HIV-positive patients on combination antiretroviral therapy areineligible because of the potential for pharmacokinetic interactionswith AZD2281. In addition, these patients are at increased risk oflethal infections when treated with marrow-suppressive therapy such ascarboplatin.

Major surgery within the past 28 days.

Patients with locally advanced breast tumors presenting for theirinitial therapy, or patients with local (only in breast or chest wall)recurrence only will not be eligible for this trial

For subjects in the dose-expansion cohorts, history of prior invasivemalignancies within the past 5 years (with the exception ofnon-melanomatous skin cancers, non-invasive bladder cancer, stage Iendometrial cancer or cervical cancer cured by surgical resection).

Example 5 Bladder Cancer

Study Type: Interventional

Study Design: Allocation: Randomized

Primary Purpose: Treatment with combination of ibrutinib and abexinostat

Objectives

I. Determine whether treatment with ibrutinib and abexinostat iseffective in preventing recurrence of tumor after transurethralresection in patients with low grade, superficial transitional cellcarcinoma of the bladder.

II. Determine the incidence and severity of toxicities associated withthe long-term use of this drug in this patient population.

Eligibility

Ages Eligible for Study: 18 Years and older

Genders Eligible for Study: Both

Accepts Healthy Volunteers: No

Criteria

Disease Characteristics

Histologically confirmed low grade (grade 1 or 2), superficial (stage Taor T1) transitional cell carcinoma (TCC) of the bladder

Newly diagnosed or recurrent

All visible tumor must have been resected within the past 12 weeks

Standard clinical management determined to be expectant observationwithout further surgery, intravesical therapy, or systemic therapy

No prior upper tract TCC

No history of grade 3 TCC, carcinoma in situ including severe dysplasia,non-TCC histology, or TCC greater than or equal to T2

No involvement of upper urinary tract prior to or at the time of initialtumor resection

Abdominal CT scan, IVP, or retrograde pyelogram within the past 3 monthsto rule out upper urinary tract tumor

Patient Characteristics

Not pregnant or nursing

Negative pregnancy test

Fertile patients must use effective contraception

No prior malignancy within the past 5 years and no concurrent malignancyexcept nonmelanomatous skin cancer or carcinoma in situ of the cervix

No clinically significant hearing loss (i.e., hearing loss effectseveryday life and/or wears a hearing aide)

No other significant medical or psychiatric condition

Example 6 Lung Cancer

Study Type: Interventional

Study Design: Allocation: Randomized

Endpoint Classification: Safety/Efficacy Study

Masking: Double Blind (Subject, Investigator)

Primary Purpose: Treatment with ibrutinib and abexinostat

Primary Outcome Measures: Immune-related Progression-free Survival(irPFS) in Participants With Nonsmall-cell Lung Cancer (NSCLC) PerImmune-related Response Criteria (irRC) [Time Frame: Tumor assessed atscreening, every 6 weeks on treatment to Week 24, and every 12 weeks onmaintenance until immune-related Progressive Disease (irPD) or death (ofcensored, maximum reached: 16.5 months)]

irPFS is defined as the time between the randomization date and date ofimmune-related Progressive Disease (irPD) (at least 25% increasepercentage change in total tumor burden, including new lesions) ordeath, whichever occurs first. For patients with no recordedpostbaseline tumor assessments, irPFS is censored at randomization.Participant who die without reported irPD are considered to haveprogressed on the date of death. For those who remain alive and have noirPD, irPFS is censored on the date of last evaluable tumor assessment.Independent review committee performed tumor assessment

Detailed Description

Patients will be treated three times daily ibrutinib (140 mg/dose) andonce daily with abexinostat for 4 consecutive days, followed by 3 daysoff of abexinostat (a cycle is 7 days). At day 1 of each cycle aphysical exam and blood work will be performed. Reassessment of tumorsize will be conducted at 6 weeks, 12 weeks and then every 9 weeksthereafter. Patients will remain on treatment until one of the followingoccur: disease progression, illness that prevents further treatment orunacceptable adverse events.

Inclusion Criteria

Histologically or cytologically confirmed lung cancer (Stage IIIb/IVnonsmall-cell lung cancer or extensive stage small-cell lung cancer[SCLC])

Measurable tumor lesion (as long as it is not located in a previouslyirradiated area) as defined by modified World Health Organizationcriteria

Eastern Cooperative Oncology Group performance status of <1 at studyentry

Accessible for treatment and follow-up

Exclusion Criteria:

Brain metastases

Malignant pleural effusion

Autoimmune disease

Motor neuropathy of autoimmune origin

SCLC-related paraneoplastic syndromes

Any concurrent malignancy other than nonmelanoma skin cancer; carcinomain situ of the cervix or breast; or prostate cancer treated withsystemic therapy (participants with a previous malignancy but withoutevidence of disease for 5 years were allowed to enter the study)

Prior systemic therapy for lung cancer. Prior radiation therapy orlocoregional surgeries performed later than at least 3 weeks prior torandomization date were allowed.

Known HIV or hepatitis B or C infection

Chronic use of immunosuppressants and/or systemic corticosteroids (usedin the management of cancer or noncancer-related illnesses). However,use of corticosteroids was allowed if used as premedication forpaclitaxel infusion or for treating immune-related adverse events oradrenal insufficiencies.

Inadequate hematologic function defined by an absolute neutrophilcount<1,500/mm^3, a platelet count<100,000/mm^3, or hemoglobin level<9g/dL.

Inadequate hepatic function defined by a total bilirubin level>2.0 timesthe upper limit of normal (ULN), or ≧2.5 times the ULN if livermetastases are present, aspartate aminotransferase and alanineaminotransferase levels≧2.5 times the ULN or ≧5 times the ULN if livermetastases are present.

Inadequate renal function defined by a serum creatinine level≧2.5 timesthe ULN

Inadequate creatinine clearance defined as less than 50 mL/min.

Example 7 Prostate Cancer

Study Type: Interventional

Study Design: Endpoint Classification: Safety/Efficacy Study

Intervention Model: Single Group Assignment

Masking: Open Label

Primary Purpose: Treatment

Primary Outcome Measures: PSA response rate with abexinostat andibrutinib therapy in androgen independent non-metastatic prostate cancer[Time Frame: An average every 6 weeks for up to 3 months]

Secondary Outcome Measures: Overall survival of androgen independentnon-metastatic prostate cancer patients treated with abexinostata ndibrutinib [Time Frame: Every 3 months]

Detailed Description

Patients will be treated three times daily ibrutinib (140 mg/dose) andonce daily with abexinostat for 4 consecutive days, followed by 3 daysoff of abexinostat (a cycle is 7 days). At day 1 of each cycle aphysical exam and blood work will be performed. Reassessment of tumorsize will be conducted at 6 weeks, 12 weeks and then every 9 weeksthereafter. Patients will remain on treatment until one of the followingoccur: disease progression, illness that prevents further treatment orunacceptable adverse events.

Eligibility

Ages Eligible for Study: 18 Years and older

Genders Eligible for Study: Both

Accepts Healthy Volunteers: No

Inclusion Criteria:

A histologic diagnosis of prostate adenocarcinoma.

No evidence of bone/visceral metastases as visualized on standardimaging such as bone scan, chest X-ray, CT scan or MRI of abdomen andpelvis.

PSA-only progression despite androgen deprivation therapy. PSAprogression is defined as 3 rising levels, with a minimum interval of 2weeks between each determination. The last determination must have aminimum value of 1 ng/ml and be determined within two weeks prior toregistration. If the second or third confirmatory value is less than theprevious value, the patient will still be eligible if a repeat value(No. 4) is found to be greater than all the prior values.

If patient has been on antiandrogen in the past 28 days, then PSAprogression after withdrawal period (28 days for flutamide and 42 daysfor bicalutamide or nilutamide) is required.

ECOG performance status of 0-1.

No investigational or commercial agents or therapies (except LHRHagonists) may be administered concurrently with the intent to treat thepatient's malignancy. Patients on LHRH agonists must continue the use ofLHRH agonist therapy. Bisphosphonates can be administered per treatingphysician discretion.

At least 4 weeks must have elapsed since prior systemic therapy, exceptfor LHRH analogue therapy and steroids. If steroids are being used fortherapy of prostate cancer, these should be discontinued prior tostarting avastin therapy.

Life expectancy of at least 6 months.

Ability to understand and the willingness to sign a written informedconsent that is approved by the Institutional Human InvestigationCommittee.

Use of effective means of contraception in subjects.

Exclusion Criteria:

Inability to comply with study and/or follow-up procedures.

Inadequately controlled hypertension (defined as systolic bloodpressure>150 and/or diastolic blood pressure>100 mmHg onantihypertensive medications).

Any prior history of hypertensive crisis or hypertensive encephalopathy.

New York Heart Association (NYHA) Grade II or greater congestive heartfailure

History of myocardial infarction or unstable angina within last 12months prior to study enrollment.

History of stroke or transient ischemic attack within 6 months prior tostudy enrollment.

Known CNS disease.

Significant vascular disease (e.g., aortic aneurysm, aortic dissection).

Symptomatic peripheral vascular disease.

Evidence of bleeding diathesis or coagulopathy.

Patients on anticoagulants are allowed if patient has been on therapyfor at least 4 weeks and patient has no acute thromboembolic activity.

Major surgical procedure, open biopsy, or significant traumatic injurywithin. 28 days prior to study enrollment or anticipation of need formajor surgical procedure during the course of the study.

Core biopsy or other minor surgical procedure, excluding placement of avascular access device, within 7 days prior to study enrollment.

History of abdominal fistula, gastrointestinal perforation, orintra-abdominal abscess within 6 months prior to study enrollment.

Serious, non-healing wound, ulcer, or bone fracture.

Proteinuria at screening as demonstrated by: Urine protein:creatinine(UPC) ratio≧1.0 at screening

Refusal to use effective means of contraception.

Patients with known brain metastases should be excluded from thisclinical trial because of their poor prognosis and because they oftendevelop progressive neurologic dysfunction that would confound theevaluation of neurologic and other adverse events.

History of allergic reactions attributed to compounds of similarchemical or biologic composition to avastin.

Uncontrolled intercurrent illness including, but not limited to, ongoingor active infection, symptomatic congestive heart failure, unstableangina pectoris, cardiac arrhythmia, or psychiatric illness/socialsituations that would limit compliance with study requirements.

Patients with immune deficiency such as HIV-positive patients or thosereceiving combination anti-retroviral therapy are excluded from thestudy because of lack of safety data for avastin in these patients.

Example 8 Bile Duct Cancer

Study Type: Interventional

Study Design: Endpoint Classification: Safety/Efficacy Study

Intervention Model: Single Group Assignment

Masking: Open Label

Primary Purpose: Treatment

Primary Outcome Measures: Overall survival with abexinostat andibrutinib therapy [Time Frame: 3 years]

Secondary Outcome Measures: Response rate defined as proportion ofpatients with complete response (CR), partial response (PR), stabledisease (SD), or progressive disease (PD), using based on the RECISTversion 1.1

Detailed Description

Patients will be treated three times daily ibrutinib (140 mg/dose) andonce daily with abexinostat for 4 consecutive days, followed by 3 daysoff of abexinostat (a cycle is 7 days). At day 1 of each cycle aphysical exam and blood work will be performed. Reassessment of tumorsize will be conducted at 6 weeks, 12 weeks and then every 9 weeksthereafter. Patients will remain on treatment until one of the followingoccur: disease progression, illness that prevents further treatment orunacceptable adverse events.

Eligibility

Ages Eligible for Study: 18 Years and older

Genders Eligible for Study: Both

Accepts Healthy Volunteers: No

Inclusion Criteria:

Histologically and cytologically proven cholangiocarcinoma of any type(including intrahepatic cholangiocarcinoma, extrahepatic primarycholangiocarcinoma, hilar cholangiocarcinomas, cholangiocarcinomaslocated in the gall bladder or hepatic capsule effraction, and carcinomaof the Ampulla of Vater, etc.) that is not amenable to surgery,radiation, or combined modality therapy with curative intent, and hasfailed or is not eligible for available chemotherapies such asgemcitabine with or without platinum

Local, locally-advanced, or metastatic disease documented as havingshown progression on a scan (e.g., computed tomography [CT], magneticresonance imaging [MRI])

Measurable tumor according to Response Evaluation Criteria in SolidTumors (RECIST) 1.1 criteria with at least one unidimensionallymeasurable target lesion

No evidence of biliary duct obstruction, unless obstruction iscontrolled by local treatment or, in whom the biliary tree can bedecompressed by endoscopic or percutaneous stenting with subsequentreduction in bilirubin to below 1.5× upper level of normal (ULN)

Eastern Cooperative Oncology Group (ECOG) performance status being 0-3

Expected survival>3 months

Women of child-bearing potential (i.e., women who are pre-menopausal ornot surgically sterile) must use accepted contraceptive methods(abstinence, intrauterine device [IUD], oral contraceptive or doublebarrier device) during the study, and must have a negative serum orurine pregnancy test within 1 week prior to treatment initiation

Fertile men must practice effective contraceptive methods during thestudy, unless documentation of infertility exists

Granulocyte count>=1500/mm^3

White blood cell (WBC)>=3500 cells/mm^3 or >=3.5 bil/L

Platelet count>=150,000 cells/mm^3 or >=150 bil/L

Absolute neutrophil count (ANC)>=1500 cells/mm^3 or >=1.5 bil/L

Hemoglobin>=9 g/dL or >=90 g/L

Aspartate aminotransferase (AST/serum glutamic oxaloacetic transaminase[SGOT])=<3× upper normal limit (UNL), alanine aminotransferase(ALT/serum glutamate pyruvate transaminase [SGPT])=<3×UNL (=<5×UNL ifliver metastases present)

Bilirubin=<1.5×UNL

Serum creatinine=<2.0 mg/dL or 177 μmol/L

International normalized ratio or INR must be =<1.5

No evidence of active infection and no serious infection within the pastmonth

Mentally competent, ability to understand and willingness to sign theinformed consent form

Exclusion Criteria:

Patients receiving any other standard or investigational treatment fortheir cancer

Serious medical illness that would potentially increase patients' riskfor toxicity

Any active uncontrolled bleeding, and any patients with a bleedingdiathesis (e.g., active peptic ulcer disease)

Pregnant women, or women of child-bearing potential not using reliablemeans of contraception

Lactating females

Fertile men unwilling to practice contraceptive methods during the studyperiod

Life expectancy less than 3 months

Unwilling or unable to follow protocol requirements

Dyspnea with moderate exertion; patients with pleural or pericardialeffusions

Active heart disease including but not limited to symptomatic congestiveheart failure, symptomatic coronary artery disease, symptomatic anginapectoris, symptomatic myocardial infarction, arrhythmias requiringmedication, or symptomatic congestive heart failure; also patients witha history of myocardial infarction that is <1 year prior toregistration, or patients with previous congestive heart failure (<1year prior to registration) requiring pharmacologic support or with leftventricular ejection fraction<50%)

A marked baseline prolongation of QT/corrected QT (QTc) interval (e.g.,repeated exhibition of a QTc interval>470 ms)

A history of additional risk factors for torsade de pointes (e.g., heartfailure, hypokalemia, family history of long QT syndrome)

Evidence of active infection, or serious infection within the past month

Patients with known human immunodeficiency virus (HIV) infection

Requirement for immediate palliative treatment of any kind includingsurgery

Patients that have received a chemotherapy regimen with stem cellsupport in the previous 6 months

Prior illicit drug addiction

Any condition or abnormality which may, in the opinion of theinvestigator, compromise the safety of the patient

Example 9 Large Cell Lung Cancer

Study Type: Interventional

Study Design: Endpoint Classification: Safety/Efficacy Study

Intervention Model: Single Group Assignment

Masking: Open Label

Primary Purpose: Treatment

Primary Outcome Measures: The proportion of subjects progression-free atMonth 3. Time Frame [Time Frame: 3 months]

Secondary Outcome Measures: the proportion of subjects progression-freeat Month 6 [Time Frame: 6 months]; overall response rate (ORR) is theproportion of patients with a best overall response of Complete Response(CR) or Partial Response (PR) at Month 3 [Time Frame: 3 months]; diseasecontrol rate (DCR) is the proportion of patients with a best overallresponse of CR or PR or Stable Disease (SD) at Month 3 (C4D21) [TimeFrame: 3 months]; progression Free Survival [Time Frame: approximately3-6 months]; overall Survival [Time Frame: estimated 12 months]

Detailed Description

Patients will be treated three times daily ibrutinib (140 mg/dose) andonce daily with abexinostat for 4 consecutive days, followed by 3 daysoff of abexinostat (a cycle is 7 days). At day 1 of each cycle aphysical exam and blood work will be performed. Reassessment of tumorsize will be conducted at 6 weeks, 12 weeks and then every 9 weeksthereafter. Patients will remain on treatment until one of the followingoccur: disease progression, illness that prevents further treatment orunacceptable adverse events.

Eligibility

Ages Eligible for Study: 18 Years and older

Genders Eligible for Study: Both

Accepts Healthy Volunteers: No

Inclusion Criteria:

Written informed consent obtained according to local guidelines

Histologically confirmed diagnosis of stage IV lung cancer of LC-NECtype according to WHO classification:

-   -   Histolocial analysis of newly diagnosed disease must not be        older than 8 weeks from signed consent    -   Relapse must be confirmed by histology    -   Neuroendocrine differentiation

3. World Health organisation (WHO) performance status grade≦1

4. measurable disease

5. Adequate bone marrow function

6. Adequate liver function

7. Adequate renal function

Exclusion Criteria:

Clinical evidence of central nervous system (CNS) metastases.

Presence of SCLC cells

Patients who have a history of another primary malignancy≦3 years, withthe exception of inactive basal or squamous cell carcinoma of the skinor cervical cancer in situ, early stages of breast cancer (LCIS andDCIS) and prostate cancer (stage T1a)

Prior chemotherapy for the treatment of advanced lung cancer and/or nothaving recovered from the side effects of any other therapy (adjuvanttreatment for earlier stages I-III is allowed if finished at least oneyear before study entry)

Treatment with any investigational drug≦28 days before starting studytreatment or who have not recovered from side effects of such therapy

Women who are pregnant or lactating.

What is claimed is:
 1. A method for treating a solid tumor comprisingadministering to an individual in need thereof,(R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one

and3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide


2. The method of claim 1, wherein the solid tumor is a carcinoma.
 3. Themethod of claim 2, wherein the carcinoma is breast cancer.
 4. The methodof claim 2, wherein the carcinoma is pancreatic cancer.
 5. The method ofclaim 2, wherein the carcinoma is colorectal cancer.
 6. The method ofclaim 2, wherein the carcinoma is bladder cancer.
 7. The method of claim2, wherein the carcinoma is lung cancer.
 8. The method of claim 7,wherein the lung cancer is a non-small cell lung cancer.
 9. The methodof claim 7, wherein the lung cancer is a large cell lung cancer.
 10. Themethod of claim 2, wherein the carcinoma is prostate cancer.
 11. Themethod of claim 2, wherein the carcinoma is ovarian cancer.
 12. Themethod of claim 2, wherein the carcinoma is bile duct cancer.
 13. Themethod of claim 1, wherein ibrutinib and abexinostat are administered ina unified dosage form or separate dosage forms.
 14. The method of claim1, wherein ibrutinib and abexinostat are administered simultaneously orsequentially.
 15. A composition comprising a therapeutically effectiveamount of(R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one

and a therapeutically effective amount of3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide

and a pharmaceutically acceptable excipient.